Templated Organic Synthesis

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

Templated Organic Synthesis Edited by Frangois Diederich and Peter J. Stang

@3 WILEY-VCH Weinheim . New York . Chichester . Brisbane . Singapore .Toronto

Templated Organic Synthesis

@ W I LEY-VCH

Templated Organic Synthesis Edited by Frangois Diederich and Peter J. Stang

@3 WILEYVCH Weinheim . New York . Chichester . Brisbane . Singapore .Toronto

Prof. Dr. F. Diederich Laboratorium fur Organische Chemie Eidgenossische Technische Hochschule ETH-Zentrum Universitatstrasse 16 CH-8092 Zurich Switzerland

Prof. Dr. P. J. Stang Department of Chemistry University of Utah Salt Lake City, UT 84112 USA

This book was carefully produced. Nevertheless, authors, editors and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.applied for. A catalogue record for this book is available from the British Library. Deutsche Bibliothek Cataloguing-in-PublicationData: A catalogue record for this book is available from Der Deutschen Bibliothek

0 WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany), 2000 Printed on acid-free and chlorine-free paper. All rights reserved (including those of translation in other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition, Printing and Bookbinding: Konrad Triltsch, D-97070 Wurzburg Printed in the Federal Republic of Germany

Related Titles from WILEY-VCH:

E Diederich / P. J. Stang (eds.)

Metal-catalyzed Cross-couplingReactions

1997. XXII. 518 pages with approx lo00 figures and 20 tables Hardcover. ISBN 3-527-29421-X

N. V Gerbeleu / V B. Arion / J, Burgess (eds.) Template Synthesis of Macrocyclic Compounds 1999. IX. 574 pages with over 300 figures and 10 tables Hardcover. ISBN 3-527-29559-3

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Preface

Templated synthesis is a timely research area where molecular and supramolecular sciences meet. Moreover, it represents an emerging interface between chemistry, biology, and materials sciences. This multi-author monograph includes authoritative contributions from ten leading research laboratories involved in the development of novel template-assisted organic synthesis at this interface. It demonstrates how non-covalent and covalent templates are successfully applied to control the rate and the regio- and stereoselectivity of molecular and supramolecular organic reactions. In view of the broad, often indiscriminate use of the words “templates” and “tethers”, the scope of the monograph requires careful definition. According to Webster ‘s Dictionary, a template is “a gauge, pattern, or mold (as a thin plate or board) used as a guide to the form of a piece being made”. The same source defines a tether as “something (as a rope or chain), by which an animal is fastened so that it can range only within a set radius”. “Mold” is perhaps the best single word to define a template in the frame of this monograph. Since clear definitions are important, it is appropriate that Chapter 1 provides definitions and describes the roles of templates in organic synthesis. Either non-covalent or covalent templates need to be absent in the original substrate as well as in the product or, at least, should be removable after having accomplished their task. Tethers should be effective in the transition states of reactions and, by acting as a mold, control the rate and the regio- and stereochemistry. Thus the monograph focuses on reactivity rather than on static structural chemistry. It is intended to promote the use of intermolecular non-covalent interactions, besides steric discrimination, to control reactivity and selectivity. Its content was selected to provide useful template- or tetherbased methodology to both expert and novice practitioners in both the molecular and supramolecular sciences. This book is focused on organic synthesis and reactivity, naturally combining and merging molecular and supramolecular aspects. It includes one contribution (Chapter 5) on templated synthesis of biological polymers and their mimics. A profound discussion of biological templated reactions or inorganic templated synthesis (such as biomineralization) is beyond the scope of this monograph. Likewise, templates (better: scaffolds) in medicinal chemistry are excluded. Thus, carbohydrates or other central scaffolds (or cores), from which functional groups for protein recognition diverge, have sometimes been named as templates. Furthermore, the concept of reversibility, i.e., the removal of a non-covalent or covalent tether after the function of providing a “mold” has been accomplished, is important. This eliminates a variety of supramolecular self-assembly processes as well as “structural templates” such as those used to organize four-helix bundle proteins. Although all metal-catalyzed reactions such as the Pauson-Khand reaction, Co-catalyzed cyclotrimerization, and metal-catalyzed cross-coupling reactions are templated

VI

Preface

reactions in which the metal center acts as template, they are excluded since they have been the subject of the previous monographs, Modern Acetylene Chemistry and Metulcatalyzed Cross-coupling Reactions from the same editors and publishers as this book. The requirement for ultimate removal of the covalent template precludes examples in which the reaction has been changed from an intermolecular to an intramolecular one by connecting the reaction partners by some kind of permanent tether which remains in the molecule. Even with this restriction, organic synthesis provides an extremely rich variety of reversible templating and tethering, as illustrated in Chapter 10; here, we would only like to mention the “silicon connection” chemistry introduced by G. Stork. Claimed template effects sometimes deserve critical mechanistic examination, and this is nicely illustrated in Chapter 9. The increasingly successful use of intermolecular interactions by non-covalent and covalent molecular and polymeric tethers provides an important link between organic synthesis and supramolecular chemistry in this monograph. Synthesis in Nature abundantly takes advantage of non-covalent bonding and templating and, therefore, the chemistry described herein can be rightly qualified as biomimetic. Emphasis is placed upon key developments and important advances, which are illustrated with attractive and useful examples. Areas covered range from molecular imprinting (Chapter 2), molecular recognition and supramolecular self-assembly (Chapters 3 and 4), biomimetic catalysis (Chapter 6 ) , templated synthesis of biopolymers and unnatural oligomers and polymers (Chapters 1, 5, and 8), regio- and stereoselective synthesis of covalent fullerene derivatives (Chapter 7), templated macrocyclizations (Chapters 1 and 9), to the use of temporary connections in organic synthesis (Chapter 10). Carefully chosen references guide the reader through the extensive literature. A useful feature is the inclusion of key synthetic protocols, in experimental format, in six chapters. We are hopeful that the monograph will stimulate the further development of efficient and exciting new templated synthesis methodology in the molecular and supramolecular sciences.

ETH Zurich University of Utah Salt Lake City May 10,1999

FranGois Diederich Peter J. Stang

List of Contributors

Jennifer R. Allen Department of Chemistry Box 1822, Station B Vanderbilt University Nashville, TN 37235 USA Harry L. Anderson Department of Chemistry Oxford University Dyson Perrins Laboratory South Parks Road Oxford OX 13QY, UK Sally Anderson Sharp Laboratories of Europe LTD Edmund Halley Road Oxford Science Park Oxford OX4 46A, UK

Ronald Breslow Department of Chemistry Columbia University New York, New York 10027 USA Liam R. Cox School of Chemistry University of Birmingham Edgbaston, Birmingham B 15 2TT UK

Prof. Frangois Diederich Laboratorium fur Organische Chemie ETH Ziirich Universitatstrasse 16, CH-8092 Ziirich Switzerland

Ken S. Feldman Department of Chemistry The Pennsylvania State University University Park, Pennsylvania 16802 USA Alois Furstner Max-Planck-Institut fur Kohlenforschung D-45470 MulheimIRuhr Germany Yahaloma Gat Searle and Jones Chemical Laboratories 5735 Ellis Avenue University of Chicago Chicago, Illinois 60637 USA Roland Kessinger Laboratorium fur Organische Chemie ETH Zurich Universitiitstrasse 16, CH-8092 Zurich Switzerland Steven V. Ley Department of Chemistry University of Cambridge Lensfield Road, Cambridge CB2 1EW UK David G. Lynn Searle and Jones Chemical Laboratories 5735 Ellis Avenue University of Chicago Chicago, Illinois 60637 USA

VIII

List of Contributors

Darren Makeiff Department of Chemistry University of British Columbia 2036 Main Mall Vancouver, BC Canada V6T 1Z1

John C. Sherman Department of Chemistry University of British Columbia 2036 Main Mall Vancouver, BC Canada V6T 1Z1

Ned A. Porter Department of Chemistry Box 1822, Station B Vanderbilt University Nashville, TN 37235 USA

J. Fraser Stoddart

Franqisco M. Raymo Department of Chemistry and Biochemistry University of California, Los Angeles 405 Hilgard Avenue Los Angeles, California 90095- 1569 USA

Department of Chemistry and Biochemistry University of California, Los Angeles 405 Hilgard Avenue Los Angeles, California 90095- 1569 USA

Gunter Wulff Institute of Organic Chemistry and Macromolecular Chemistry Heinrich-Heine-University of Dusseldorf Universitatstrasse 1, D-40225 Diisseldorf Germany

List of Abbreviations

A AbZ acac ACT AIBN ATPH BINOL Bn Boc, BOC BOM BSA CAN Cbz CD CDB COD CP CSA CTAB CY D DBU DCC DCE DDQ d.e. DIBALH DICI DIPEA DMA DMAD DMAP DME DMF DMSO DMTr DMTST

acceptor; adenine N6-benzoyladenine acetylacetonate addition, cyclization, transfer

2,2’-azobis(isobutyronitrile) aluminum tris(2,6-diphenylphenoxide) l,l’-binaphthalene-2,2’-diol benzyl tert-butyloxycarbony1 benzyloxymethyl N, 0-bis(trimethylsi1y1)acetamide cerium(1V) ammonium nitrate benzyloxycarbonyl circular dichroism charged hydrogen bond 1,5-~yclooctadiene cyclopentadienyl camphorsulfonic acid cetyl triethylammonium bromide cyclohexyl donor

1,8-diazabicyclo[5.4.O]undec-7-ene N,N‘-dicyclohexylcarbodiimide 1,2-dichloroethane 2,3-dichloro-5,6-dicyanobenzoquinone diastereomeric excess diisobutylaluminum hydride N,N’-diisoprop ylcarbodiimide diisopropylethylamine N,N-dimethylacetamide; 9,lO-dimethylanthracene (Chapter 7) dimethyl acetylenedicarboxylate

4-(dimethy1amino)pyridine 1,2-dimethoxyethane N,N-dimethylformamide dimethyl sulfoxide 4,4'-dimethox ytriphen ylmeth y l dimethyl(methy1thio)sulfonium trifluoromethanesulfonate

X

List of Abbreviations

deoxyribonucleic acid difference nuclear Orerhauser effect 3-hydroxy-~-tyrosine bis(dipheny1phosphino)ethane differential scanning calorimetry 2,6-di-tert-butylpyridine ethylenediaminetetraaceticacid enantiomeric excess effective molarity (9H-fluoren-9-y1methoxy)carbonyl gas chromatography guest determining step { 'H-13C}heteronuclear shift correlation hexamethyldisilazane hexamethylphosphoric triamide 1-hydroxy- lH-benzotriazole high-performance liquid chromatography; high-pressure liquid chromatography (Chapter 8) homo-RNA h-RNA iodonium collidine perchlorate IDCP iodonium collidine triflate IDCT intramolecular Diels -Alder IMDA isopropanol i-PrOH potassium hexamethyldisilazide KHMDS lithium diisopropylamide LDA locked-nucleic acid LNA L-selectride lithium tri-sec-butylborohydride lowest unoccupied molecular orbital LUMO Monte Car10 MC m-chloroperoxybenzoic acid mCPBA methyl methacrylate MMA 4-methoxytriphenylmethyl MMTR methoxymethyl MOM molecular sieves ms norbornadiene NBD N-bromosuccinimide NBS N-iodosuccinimide NIS N-formylpiperidine NFP N-methylmorpholine N-oxide NMO N-methyl-2-pyrrolidinone NMP oxypeptide-RNA OPNA trifluoromethane sulfonate OTf pyridinium chlorochromate PCC pyridinium dichromate PDC

DNA DNOE L-DOPA dPPe DSC DTBP EDTA e.e. EM Fmoc GC GDS HETCOR HMDS HMPA HOBT HPLC

List of Abbreviations PEG phen Phth Piv PM3 PMB pMMA PNA

Pr pRNA pTSA PY Ra-Ni RCM RNA RORCM rSNA rt RVC SDDS T TBAF TBDMS TBDPS TBS Tf TFA

THF THP

TLC TMP TMS TMSI Tr Ts TsOH T. S. TSA

poly(ethy1ene glycol) 1,lO-phenanthroline phthalyl pivaloyl parametric method 3 p-methoxybenzy1 poly(methy1 methacrylate) peptide-nucleic acid ProPYl pyranosyl-RNA p-toluenesulfonic acid pyridine Raney nickel ring-closing metathesis ribonucleic acid ring-opening and ring-closing metathesis dimethylene sulfone RNA room temperature reticulated vitreous carbon sodium dodecylsulfate thymine tetrabutylammonium fluoride rert-butyldimethylsilyl tert-butyldiphenylsilyl tert-butyldimethylsilyl trifluoromethane sulfonyl trifluoroacetic acid tetrahydrofuran 3,4,5,6-tetrahydro-2H-pyran-2-~1 thin layer chromatography tetramethylpiperidine trimethylsilyl trimethylsilyl iodide triphenylmethyl p-toluenesulfon yl p-toluenesulfonic acid transition state p-toluenesulfonic acid

XI

Contents

1

Templates in Organic Synthesis: Definitions and Roles Sally Anderson, Harry L. Anderson

1.1

Introduction - Early Templates . . . . . . . . . . . . . . . . . . . .

1

1.2

The Definition of a Molecular Template . . . . . . . . . . . . . . .

4

1.3 1.3.1 1.3.2 1.3.3 1.3.3.1 1.3.3.2 1.3.3.3 1.3.4 1.3.5

Roles of Templates . . . . . . . . . . . . . . . . . . . . . . . . . . Thermodynamic and Kinetic Templates . . . . . . . . . . . . . . . Covalent and Non-covalent Template-Substrate Interactions . . . . Topology of Reaction . . . . . . . . . . . . . . . . . . . . . . . . Cyclization templates . . . . . . . . . . . . . . . . . . . . . . . . Linear templates . . . . . . . . . . . . . . . . . . . . . . . . . . . Interweaving templates . . . . . . . . . . . . . . . . . . . . . . . . Scavenger Templates . . . . . . . . . . . . . . . . . . . . . . . . . Negative Templates . . . . . . . . . . . . . . . . . . . . . . . . .

5 5

1.4 1.4.1 1.4.2

Measuring Template Effects . . . . . . . . . . . . . . . . . . . . . Qualitative Detection of Template Effects . . . . . . . . . . . . . . Quantification of Kinetic Template Effects in Terms of Effective Molarity, Substrate Affinity, and Maximum Rate Enhancement . . . Linear templates . . . . . . . . . . . . . . . . . . . . . . . . . . . Quantitative analysis of template effects in tethered reactions . . . Cyclization templates . . . . . . . . . . . . . . . . . . . . . . . .

22 23 29 29

1.5

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Appendix la: Equations for Figure 1-5 . . . . . . . . . . . . . . . Appendix lb: Equations for Figure 1-10 . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33 34 34 35

2

Templated Synthesis of Polymers - Molecularly Imprinted Materials for Recognition and Catalysis

1.4.2.1 1.4.2.2 1.4.2.3

8 9 10 14 18 19 20

21 21

Gunter Wulff 2.1

Introduction

.............................

39

2.2

Preparation of Optically Active Linear Vinyl Polymers by Templated Synthesis . . . . . . . . . . . . . . . . . . . . . . .

40

XIV

Contents

2.3

Exact Placement of Functional Groups on the Surfaces of Rigid Polymeric Materials Using Template Molecules . . . . . . . . . . .

2.4 2.4.1 2.4.2 2.4.3 2.4.4 2.4.5 2.4.6 2.4.7

Molecular Imprinting in Polymeric Materials Using Template Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Optimization of the Structure of the Polymer Network . . . . . The Role of the Binding-site Interactions . . . . . . . . . . . . . . Chiroptical Properties of the Crosslinked Polymers . . . . . . . . . Chromatography Using Molecularly Imprinted Polymers . . . . . . Catalysis With Molecularly Imprinted Polymers . . . . . . . . . . Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5 2.5.1 2.5.1.1 2.5.1.2 2.5.2 2.5.2.1 2.5.2.2 2.5.3 2.5.3.1 2.5.3.2 2.5.3.3 2.5.4

Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . . Polymer from Scheme 2-5 . . . . . . . . . . . . . . . . . . . . . . Preparation of template monomer 7 [34] . . . . . . . . . . . . . . . Preparation of the polymer E351 . . . . . . . . . . . . . . . . . . . Polymer from Scheme 2-6 . . . . . . . . . . . . . . . . . . . . . . Thermally initiated polymerization [36] . . . . . . . . . . . . . . . Photochemically initiated polymerization [50] . . . . . . . . . . . Polymer from Scheme 2-9 [136. 1371 . . . . . . . . . . . . . . . .

3

Ternplated Synthesis of Catenanes and Rotaxanes

N-Ethyl-4-vinylbenzamide . . . . . . . . . . . . . . . . . . . . . . N-Ethyl-4-vinylbenzocarboximideacidethylester . . . . . . . . . N,N’.Diethyl. 4.vinylbenzamidine ( 1Oa) . . . . . . . . . . . . . . . Preparation of the polymer [ 1121 . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42 45 45 50 52 57 58

60 64 65 65 65 66 66 66 66 67 67 67 67 68 68

Frangisco M . Raymo. J . Fraser Stoddart

3.2

............................. Metal-Templated Syntheses . . . . . . . . . . . . . . . . . . . . .

76

3.3

Hydrogen Bonding-assisted Syntheses . . . . . . . . . . . . . . . .

78

3.4

................. Aromatic Templates . . . . . . . . . . . . . . . . . . . . . . . . . Dialkylammonium-containing Rotaxanes . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . . [2]Catenane 4 [ 131 . . . . . . . . . . . . . . . . . . . . . . . . . . [2]Catenane 12 [16] . . . . . . . . . . . . . . . . . . . . . . . . .

81

3.1

3.5 3.6 3.7 3.8 3.8.1 3.8.2

Introduction

Hydrophobically Driven Syntheses

75

84

91 95 95 95 96

Contents

......................... .........................

3.8.3 3.8.4 3.8.5 3.8.6

[2]Catenane 43 [3 1J [2]Rotaxane 51 [38] [2]Rotaxane 56 [381 [2]Rotaxane 68 1451 References . . . . .

4

Templated Synthesis of Carceplexes. Hemicarceplexes. and Capsules

......................... .........................

.........................

xv 96 96 97 97 97

Darren Make@ John C. Sherman 4.1 4.2 4.2.1 4.2.1.1 4.2.1.2 4.2.1.3 4.2.2 4.2.2.1 4.2.2.2 4.2.3 4.2.4 4.2.5 4.3 4.3.1 4.3.2 4.4 4.4.1 4.4.2 4.4.2.1 4.4.3 4.4.4 4.4.5 4.5

............................. Carceplexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The First Soluble Carceplex . . . . . . . . . . . . . . . . . . . . . Introduction

105

Template ratios in the formation of an acetal-bridged carceplex . . Formation of a charged hydrogen bonded complex . . . . . . . . . Mechanism of formation for an acetal-bridged carceplex . . . . . . Large Carceplexes from Cyclic Arrays of Cavitands . . . . . . . . Synthesis of a trimer carceplex containing three DMF molecules . . Synthesis of a bis(carcep1ex) . . . . . . . . . . . . . . . . . . . . . Benzylthia-bridged Carceplex . . . . . . . . . . . . . . . . . . . . Calix[4]arene-Cavitand Hybrid Carceplexes . . . . . . . . . . . . Metal-bridged Carceplexes . . . . . . . . . . . . . . . . . . . . . .

106 106 106 107 108 109 110 110 111 112 113

Hernicarceplexes . . . . . . . . . . . . . . . . . . . . . . . . . . . Template Effects in the Formation of a Trismethylene-Bridged Hemicarceplex . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hemicarceplexes Containing Four Slotted Portals . . . . . . . . . .

114 114 115

Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Capsules Composed of Cavitands Linked via Covalent Bonds or Charged Hydrogen Bonds . . . . . . . . . . . . . . . . . . . . . Rehek’s “Tennis Balls”. “Softhalls”. and “Wiffle Balls” . . . . . . Template effects of solvent in the synthesis of “softball” dimers . . Other Hydrogen Bonded Capsules . . . . . . . . . . . . . . . . . . Capsules that do not Involve Hydrogen Bonding . . . . . . . . . . Other Capsules . . . . . . . . . . . . . . . . . . . . . . . . . . . .

118 119 122 123 125 126

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

127 127

118

XVI

Contents

5

Template-DirectedLigation: Towards the Synthesis of Sequence Specific Polymers Yahaloma Gat. David G. Lynn

.............................

5.1

Introduction

5.2

Template-directed Ligation: Minimalist Scheme

5.3

Catalytic RNA and DNA . . . . . . . . . . . . . . . . . . . . . . .

136

5.4 5.4.1 5.4.2 5.4.3 5.4.4

Molecular Recognition . . . . . . . . . . . . . . . . . . . . . . . . Sugar Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . Phosphate Substitution . . . . . . . . . . . . . . . . . . . . . . . . Neutral Acyclic Backbones . . . . . . . . . . . . . . . . . . . . . Peptide-Peptide Association . . . . . . . . . . . . . . . . . . . . .

137 137 138 142 144

5.5

Ligation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

146

5.6

Product Dissociation

......................... Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

149

5.7

6

. . . . . . . . . .

133 134

152 153

Biomimetic Reactions Directed by Templates and Removable Tethers Ronald Breslow

.............................

6.1

Introduction

6.2

Biomimetic Reactions Using Covalently Linked Tethers and Templates . . . . . . . . . . . . . . . . . . . . . . . . . . . . Photochemical Functionalizations by Tethered Benzophenones . . . Free-radical Halogenations by Tethered Reagents . . . . . . . . . . Free-radical Reactions Directed by Tethered Templates the Radical Relay Mechanism . . . . . . . . . . . . . . . . . . . . Selective Intramolecular Epoxidations Directed by Removable Tethers . . . . . . . . . . . . . . . . . . . . . . . .

6.2.1 6.2.2 6.2.3 6.2.4 6.3 6.3.1 6.3.2 6.3.3 6.3.4

Selective Reactions Directed by Non-covalently Linked Templates Selective Aromatic Substitution Directed by Cyclodextrin Complexing . . . . . . . . . . . . . . . . . . . . Photochemical Functionalizations by Complexed Benzophenones and Chlorinations Directed by Ion-paired Templates . . . . . . . . Oxidations Directed by Metalloporphyrin and Metallosalen Templates . . . . . . . . . . . . . . . . . . . . . Other Reactions Catalyzed by Coordinated Template Catalysts . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

159 160 160 163 164 171 172 172 174 177 183 185

Contents

XVII

~~

7

Regio- and StereoselectiveMultiple Functionalization of Fullerenes Fraqois Diederich. Roland Kessinger

7.1 7.2

............................. Anthracenes as Reversible Covalent Templates . . . . . . . . . . . Introduction

.

7.3.4 7.3.5

Tether-directed Remote Functionalizations of C.. . . . . . . . . . . The First Tether-directed Multiple Functionalization of C, Formation of Higher Adducts with Novel Addition Patterns . . . . The Bingel Macrocyclization . . . . . . . . . . . . . . . . . . . . Formation of cis-2 bis-adducts . . . . . . . . . . . . . . . . . . . . Formation of cis-3 bis-adducts . . . . . . . . . . . . . . . . . . . . Other bis-functionalization patterns . . . . . . . . . . . . . . . . . Formation of Bis-adducts by Double Diels-Alder Addition ............... of Tethered Bis(buta.1. 3.diene)s to C, Double [3+2]Cycloaddition of Tethered Vinylcarbenes . . . . . . . Double [3+2]Cycloadditions of Tethered Bis-azides . . . . . . . .

7.4

Conclusions

7.3 7.3.1 7.3.2 7.3.2.1 7.3.2.2 7.3.2.3 7.3.3

7.5 7.5.1 7.5.2 7.5.3 7.5.4 7.5.5 7.5.6

8

............................. Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . .

Preparation of Hexakis-adduct 11 using DMA as a Template (Scheme 7-2) 1201 . . . . . . . . . . . . . . . . . . . . . . . . . . Preparation of Bis-adduct 24 by Reaction of Methano[60]fullerenecarboxylic Acid 2 1 with the Tether-Reactive-group Conjugate 22 (Scheme 7-4) [47] . Preparation of Tris-adduct 28 by Addition of the Anchor-TetherReactive-group Conjugate 27 to c60 (Scheme 7-4) [47] . . . . . . . Formation of Tetrakis-adduct 20 by Removal of the Tether in Hexakis-adduct 30 and Transesterification (Scheme 7-5) [2] . . . Bingel Macrocyclization: Synthesis of cis-2 Bis-adduct 42 Starting from Benzene- 1.2.dimethanol (Scheme 7-8) [25] . . . . . . . . . . Enantioselective Synthesis of cis-3 Bis adduct (fC)-2 by Bingel Macrocyclization of (S.S).66 with c60 Followed by Transesterification (Scheme 7-11) [25] . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

189 189 192 193 196 200 202 204 205 209 210 211 212 212 212 213 213 213 214 214

Template Controlled Oligomerizations Ken S . Feldman. Ned A . Portel; Jennifer R.Allen

.............................

8.1

Introduction

8.2

Controlled Oligomerizations with Tethered Monomers

.......

219 221

XVIII

Contents

8.2.1 8.2.2 8.2.3

Templates for n = 2 Telomers . . . . . . . . . . . . . . . . . . . . . Templates for n = 4 Telomers . . . . . . . . . . . . . . . . . . . . . Ether-based Templates . . . . . . . . . . . . . . . . . . . . . . . .

221 223 228

8.3 8.3.1 8.3.2 8.3.3 8.3.4 8.3.5

Controlled Oligomerizations with a Polynorbornane-based Template Template Design and Synthesis . . . . . . . . . . . . . . . . . . . Measuring the Initiator-Terminator Gap in Molecular Terms . . . . Model Studies for Optimizing Terminator Performance . . . . . . . Template Controlled Oligomerization Studies . . . . . . . . . . . . Mechanistic Studies: Probing Bimolecular Termination and Solvent Effects . . . . . . . . . . . . . . . . . . . . . . . . . .

230 231 235 236 237

8.4

Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . .

243

8.5 8.5.1

Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . . (2R.4S). and (2S,4S).2.(5.Bromopentyl).2.methyl.3.acryloy I. 4-tert-butyl oxazolidine (23) . . . . . . . . . . . . . . . . . . . . . 1,2.Bis.[3,4.bis.(5.(2R.methyl.3.acryloyl.4~.ter~.buty 1. 2-oxazolidinyl)-pentyloxy)]-ethane (24) . . . . . . . . . . . . . . . Typical conditions for ACT reaction (2SA/80'/200S") . . . . . . . . Telomer assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis of Template Diester 48 . . . . . . . . . . . . . . . . . Controlled Oligomerization of Methyl Methacrylate with Template 63 . . . . . . . . . . . . . . . . . . . . . ..... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

244

8.5.2 8.5.3 8.5.4 8.5.5 8.5.6

9

,

239

244 244 245 245 245 246 247

Templated or Not Templated. That is the Question: Analysis of Some Ring Closure Reactions Alois Fiirstner

9.2

...... Possible Pitfalls . . . .

9.3

Titanium-induced Intramolecular Carbonyl Coupling Reactions

. .

253

9.4

Zinc versus Samarium Mediated Reformatsky Reactions . . . . . .

258

9.5

Macrocycle Syntheses by Ring Closing Metathesis (RCM) . . . . .

259

9.6

Macrocycles via Tsuji-Trost Allylation . . . . . . . . . . . . . . .

265

9.7

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

268

9.8 9.8.1

Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . . Synthesis of 15,16-Dipheny1- 1,4,7,10-tetraoxa( 10.2)[20]paracyclophan- 15-ene (14, Scheme 9-8) by an Intramolecular McMurry Coupling under "Salt Free" Conditions [ 191 . . . . . .

269

9.1

Introduction

. . . . .

249

. . . . .

251

269

XIX

Contents

9.8.2 9.8.3

Synthesis of Oxacyclohexadec-11-en-2-one(22. Scheme 9- 14) via RCM [32] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Palladium-catalyzed Alkenyl Epoxide Cyclization: Synthesis of Macrocycle 39 (Scheme 9-22) 1421 . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10

Use of the Temporary Connection in Organic Synthesis

269 269 270

Liam R. Cox. Steven K Ley

10.1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

275

Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . [4+2j The Diels- Alder Reaction . . . . . . . . . . . . . . . . . . . Type 1 IMDA reactions . . . . . . . . . . . . . . . . . . . . . . . . Type I1 LMDA reactions . . . . . . . . . . . . . . . . . . . . . . . Other Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . An efficient synthesis of (-)-detoxinine using a tandem [4+2]/[3+2] reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.2.3 Sulfur tethers in [5+2] cycloaddition . . . . . . . . . . . . . . . . . 10.2.2.4 Azomethine ylides . . . . . . . . . . . . . . . . . . . . . . . . . .

277 277 278 295 299

10.3 10.3.1 10.3.2 10.3.2.1 10.3.2.2 10.3.2.3 10.3.3 10.3.4 10.3.5 10.3.6

Temporary Tethering Strategies in Radical Cyclization Reactions . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Silyl Ethers Containing the Radical Precursor . . . . . . . . . . . . The a-(bromomethy1)dimethylsilyl ether in radical cyclizations . . Other (haloalky1)dimethylsilylethers . . . . . . . . . . . . . . . . Dimethylsilyl ethers possessing alkenyl and aryl radical precursors Silyl Ethers Containing the Radical Acceptor . . . . . . . . . . . . Silyl Acetals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acetal Tethers in Radical Cyclizations . . . . . . . . . . . . . . . . Tether-directedRadical Cyclization Approaches to the Synthesis of C-Glycosides . . . . . . . . . . . . . . . . . . . . . . . . . . .

307 307 308 308 318 32 1 323 327 331

10.4

Use of the Temporary Connection in 0-Glycosylation and Nucleosidation . . . . . . . . . . . . . . . . . . . . . . . . . . Tether-Directed 0-Glycosylation . . . . . . . . . . . . . . . . Directed Nucleosidations . . . . . . . . . . . . . . . . . . . . . . .

10.2 10.2.1 10.2.1.1 10.2.1.2 10.2.2 10.2.2.2

10.4.1 10.4.2 10.5 10.5.1 10.5.2 10.5.3 10.5.4 10.5.5

..

Tether-mediatedNucleophile Delivery . . . . . . . . . . . . . . . . Synthesis of (+)-Hydantocidin . . . . . . . . . . . . . . . . . . . . Synthesis of Lincomycin . . . . . . . . . . . . . . . . . . . . . . . Intramolecular Allylation - Use in the Synthesis of Tricyclic PLactam Antibiotics . . . . . . . . . . . . . . . . . . Synthesis of Corticosteroids . . . . . . . . . . . . . . . . . . . . . Synthesis of (-)-a-Kainic Acid . . . . . . . . . . . . . . . . . . .

300 303 304

333 337 337 354 356 356 357 358 359 361

xx

Contents

10.6

Silicon-tethered Ene Cyclization . . . . . . . . . . . . . . . . . . .

362

10.7

10.7.1 10.7.2 10.7.3 10.7.4

Intramolecular Hydrosilyiation and Related Reactions . . . . . . . Hydrosilylation of Olefins . . . . . . . . . . . . . . . . . . . . . . Hydrosilylation of Acetylenes . . . . . . . . . . . . . . . . . . . . Directed Bis-Silylation Reactions . . . . . . . . . . . . . . . . . . Intramolecular Hydrosilylation of Ketones . . . . . . . . . . . . .

364 364 368 369 370

10.8

Olefination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

371

10.9

.......................... Use of the Temporary Connection in Carbenoid Chemistry . . . . . The Temporary Sulfur Connection . . . . . . . . . . . . . . . . . . Metathesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dotz Benzannulation . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . Experimental Procedures . . . . . . . . . . . . . . . . . . . . . . .

373

10.I0

10.11 10.12 10.13

10.14 10.15

Ullmann Coupling

10.16 10.16.1 Use of an Acetal Tether in Diels-Alder Reactions: IMDA Reaction of Dimethyl Acetal 28 (Scheme 10-9)[ 151 . . . . . 10.16.1.1Tether formation . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.16.1.2IMDA reaction and tether cleavage . . . . . . . . . . . . . . . . . 10.16.2 Use of a Boronate Tether in Diels-Alder Reactions: IMDA Reaction between Anthrone 50 and Methyl 4-Hydroxybut-2-enoate 3 (Scheme 10-19)[20a] . . . . . . . . . . . . . . . . . . . . . . . . 10.16.2.1Tether formation and IMDA reaction . . . . . . . . . . . . . . . . 10.16.2.2Tether cleavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.16.3 Use of the (Bromomethy1)dimethylsilyl Ether Group in a Radical Cyclization in the Synthesis of Talaromycin A, 140 [54] . . . . . . 10.16.3.1Tether formation . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.16.3.2Radical cyclization and tether cleavage (Scheme 10-47) . . . . . . 10.16.4 Use of Acetals in Intramolecular O-glycosylation: lSynthesis of ethyl 2,3,6-Tri-O-benzy1.4.0-(3,4,6-tri-O-benzy /?-D-mannopyranosy1)-a-D-glucopyranoside 246 (Scheme 10-77)[89c] . . . . . . . . . . . . . . . . . . . . . . . . 10.16.4.1Tether formation . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.16.4.2Glycosylation and tether cleavage . . . . . . . . . . . . . . . . . .

376 377 380 381 382 384 385 385 385 385 386 386 386 386 386 386

..............................

387 387 387 387

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

397

References

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

1 Templates in Organic Synthesis: Definitions and Roles Sally Anderson, Harry L. Anderson 1.1 Introduction - Early Templates The word “template” originated among mediaeval architects, builders, stonemasons, and craftsmen. A template was a full-scale pattern or mold, made of wood or metal, used as a guide when cutting stone, molding plaster, or building archways [l]. Figure 1.1 shows craftmen using templates in the 13th century [2]. At that time, most craftsmen were illiterate and templates were used to communicate and record design specifications [3]. Templates convey information. They are not permanently incorporated into the structures which they specify. They can be reused. When a template is used to build a stone arch (Figure 1.2), it holds the stones in place while they are cemented together, then it is removed to leave the free-standing structure. Chemists, the architects and builders of the molecular world, have learnt to use templates in an identical fashion. Molecular templates are control elements which favor the formation of a single product from a reactant, or reactants, that has, or have, the potential to assemble and react in a variety of ways.

Figure 1-1 Thirteenth century stonemasons, from a woodcut of a stained glass window in Chartres Cathedral (France) by E. Viollet-Leduc [2]. The templates used for building arches and stone moldings are depicted above the heads of the craftsmen.

2

1 Templates in Organic Synthesis: Definitions and Roles

Figure 1-2 The template (in black) is used to hold stone blocks in place while they are cemented together; the template is removed from the finished archway.

Molecular templates are ubiquitous in Nature. DNA is a template for RNA, which in turn is a template for protein. The idea of using molecular templates in synthesis dates from about the time Watson and Crick 14) deduced the structure of double stranded DNA (1953). Biochemistry provided the inspiration for this concept in chemical synthesis, although it was first applied to artificial systems by coordination chemists. The challenge of emulating the exquisite selectivity of biological templates was proclaimed by Todd [5] in 1956, when he suggested that templates might one day be used to control synthesis in the laboratory just as-they do in Nature. With hindsight, we can see that chemists had made serendipitous use of templates in organic reactions as early as 1926 [6], but without recognizing the significance, or generality, of the template effect.

HYo

1*+

Scheme 1-1 Condensation of 2-aminobenzaldehyde in the presence of zinc(I1) chloride leads to the tetrameric macrocycle 2.

Early work involved the use of metal cations as templates in macrocyclization reactions. Seidel [6] reacted 2-aminobenzaldehyde 1 with anhydrous zinc chloride (Scheme 1-l), but did not recognize that he had prepared the macrocycle 2, and it was not until 40 years later that Busch [7] and co-workers elucidated the structure of this type of macrocycle and investigated how metal cations template its formation.

1.1 Introduction - Early Templates

3

In 1932, a dark blue by-product was isolated during the industrial production of phthalimide from phthalic anhydride and ammonia in an iron vessel. This unexpected by-product was eventually identified as iron(I1)phthalocyanine:Now we know that the iron had templated the formation of this macrocycle [8]. Curtis investigated the condensation of acetone 4 and 1,2-diaminoethane 3 in the presence of metal cations and showed that the macrocycles 5 and 6 could be prepared both by templated and untemplated processes (Scheme 1-2)[9, 101.

Scheme 1-2 Nickel(I1) salts template the formation of tetraazamacrocycles 5 and 6 from 1.2diaminoethane and acetone.

Another celebrated example of the template effect is the synthesis of crown ethers by Pedersen [ 111, but it was Busch who first intentionally used templates in synthesis and who first articulated the concept of the “template effect” in the 1960s [12].Busch used the reaction of a nickel(I1) dithiolate complex 7 with 1,2-bis(bromomethyl)benzene 8 to illustrate his ideas (Scheme 1-3) [ 131. Once one end of the 1,2-bis(bromomethyl)benzene has reacted with the nickel complex, the nickel template induces the reactive ends of the intermediate 9 to come into close proximity and favors cyclization. The metal template allows the synthesis of a metallated macrocycle 10; the free ligand cannot be prepared by the reaction of 1,2-bis(bromomethyl)benzene with the unbound thiol (in the absence of a template other cyclic and acyclic products are formed).

+

Scheme 1-3 Nickel(I1) as a macrocyclization template.

-

X

N’

Br-

(s>N<+

‘N

4

I Templates in Organic Synthesis: Definitionsand Roles

In this chapter, we will show how the concept of template-directed organic synthesis has expanded so that now metal-ligand binding, hydrogen bonding, n- n interactions, and covalent bonding can all be exploited to allow the synthesis of molecules with a remarkable degree of control. Several detailed reviews of molecular templates have been published [ 14-20]. This chapter explores the definition and classification of molecular templates and discusses how their performance can be quantified and optimized.

1.2 The Definition of a Molecular Template The word “template” is used widely in chemistry, biochemistry, and materials science; its use has spread dramatically since the 1960s, particularly since 1990. What do we mean by a template in the context of organic synthesis? Busch gave the following definition [21]: A chemical template organizes an assembly of atoms with respect to one or more geometric loci, in order to achieve a particular linking of atoms.

This very general definition emphasizes the essential features of a template: (a) it organizes an assembly of atoms in a specific spatial arrangement, (b) it favors the formation of a single product where the possibility of forming more than one exists, and (c) it is more than just a platform onto which a structure is built - it must promote attractive interaction between the units which are ordered around it. In the context of organic synthesis this interaction is usually covalent; however, the strength of interaction induced by the template is continuously variable, as discussed later. Reagents and catalysts also influence the course of a reaction; the distinction between a template and a reagent is that a template intervenes in the spatial arrangement of atoms, rather than in the intrinsic chemistry. The template provides instructions for the formation of a single product from a substrate, or substrates, which otherwise have the potential to assemble and react in a variety of ways. Changing the template should result in a different substrate assembly and consequently a different product. In general, after the template has directed the formation of the product, it is removed to yield the template-free product, although sometimes the template becomes inextricably locked into the structure it helps to create. The use of templates (both molecular and supramolecular) has also become a popular synthetic strategy in materials science. For example, organic cations template the formation of zeolites [22], surfactant mesophases template the synthesis of mesoporous solids [231, track-etched pores in membranes template the formation of metal nanocylinders [24], and colloidal silica particles template the synthesis of photonic crystals [25]. Molecular templates are also used widely in biology and biochemistry, but these enzyme catalyzed processes are outside the scope of this review.

1.3 Roles of Templates

5

1.3 Roles of Templates 1.3.1 Thermodynamic and Kinetic Templates Busch classified templates as thermodynamic [ 13a, 271 or kinetic [ 13b, 281. A thermodynamic template shifts the position of equilibrium of a reversible reaction by preferentially binding one product. Kinetic templates operate on irreversible reactions by stabilizing the main transition states leading to the desired product. Kinetic templates almost invariably bind the product more strongly than the starting material, so they also favor the formation of the product thermodynamically. Conversely, thermodynamic templates are likely to accelerate formation of the product by transition state stabilization, so classification of the observed effect depends crucially on the reaction conditions and time scale. Kinetic templates are more difficult to design and understand but they are ultimately more versatile than thermodynamic templates. A thermodynamic template needs only to bind the desired product more strongly than other species in the reaction mixture. The criteria for an efficient kinetic template are more complex; it needs to bind all the key transition states through which the reaction proceeds, lowering their energies, thus creating a well defined channel in the energy landscape, so that the reaction is prevented from following unwanted paths. By considering how enzymes work, we can see how they resemble templates. Enzymes increase the speed and specificity of a reaction in three ways: a) Enzymes lower AH* for a reaction by stabilizing positive and negative charges as they develop during the course of the reaction and by modifying the substrate so as to enhance reactivity. b) Enzymes lower AS* for a reaction by increasing the proximity of reactive groups and control the specificity of the reaction by binding substrates in specific orientations. c) Enzymes achieve catalytic turnover by binding the transition state more strongly than the substrates or the products. Kinetic templates recognize and bind a species during a reaction in such a way as to favor a particular geometry and orientation of reactive groups, so inducing the reaction to proceed towards a single product. Thus they mimic one important feature of enzymic catalysis: by binding substrates in close proximity, they lower AS* for a reaction. The most economical template would also be catalytic by showing complementarity only to the transition state, but most templates bind strongly to their products and so exhibit little, or no, catalytic turnover. Most of the templates discussed in this chapter are kinetic templates. Some of the early examples of metal cation templated macrocyclization studied by Curtis and Busch [7,9] (Schemes 1-1 and 1-2) are thought to operate under thermodynamic control. The clearest evidence for a thermodynamic template effect comes when the template-free product is not stable under the reaction conditions. For example, treatment of 1,2-dicyanobenzene 11 with boron trichloride or uranyl chloride results in the formation of subphthalo-

6

1 Templates in Organic Synthesis: Definitions and Roles

cyanine 12 [29a] or superphthalocyanine 13 [29b] complexes, respectively (Scheme 1-4), but when the metals are removed from these macrocycles, they transform into normal phthalocyanine 15. Reaction of subphthalocyanine 12 with diiminoisoindolines such as 14 provides a useful route to unsymmetrically substituted phthalocyanines [29c-el. Subphthalocyanines and superphthalocyanines only exist as their boron and uranium complexes, respectively, whereas normal phthalocyanines exhibit a wide variety of metal complexes.

\

U0~Cl2,17O0C

11

12

14

NH

Scheme 1-4 Boron and uranyl templates direct the formation of sub- and superphthalocyanines respectively (12 and 13).Removing the template results in the formation of the normal phthalocyanine (15).

An elegant example of thermodynamic templating has been reported by Lynn and coworkers [30]. The reversible reaction of amine 16 with aldehyde 17 to give hexanucleotide imine 19 is favored by a hexanucleotide template 18 (Scheme 1-5). The imine can then be reduced to the corresponding amine 20 to “fix” the new hexanucleotide and remove it from the thermodynamic cycle. The hexanucleotide template 18 has a catalytic role in this overall process because, amazingly, it binds 19 about lo6 times more strongly than 20, so product inhibition is not a problem. (Systems of this type are described in detail in Chapter 5.)

--

7

/p

@

16

1.3 Roles of Templates

H3N HC 3'dCpGpT' \dTpGpCS'

17

+

18

HO-dGpCpApApCpG-OH

--

thermodynamic cycle

0

HN=CH

19

+

18

substrates 16 + 17

f

KBHaCN

kinetic cycle

18

+

Scheme 1-5 Catalytic and thermodynamic cycles for the DNA catalyzed reductive amination in 0.5 M NaCl at pH 6 and 25 "C.

Another interesting example of a thermodynamic template is adamantanecarboxylate 21 in the reaction shown in Scheme 1-6, discovered by Fujita and co-workers [31]. Cage 24 is only formed in very low yield, as part of an intractable mixture of oligomeric products, when 22 and 23 are mixed. When four equivalents of the template 21 are added, the equilibrium shifts towards 24 and the 1 :4 complex is the only species observable by 'HNMR. The cage 24 remains intact after the templates have been removed by acidification and solvent extraction, and is kinetically stable at room temperature.

8

I Templates in Organic Synthesis: Definitions and Roles

+

21 t

Scheme ,6 Four adamantanecarboxylatestemplate the formation of cage 2’

1.3.2 Covalent and Non-covalent Template-Substrate Interactions Templates can be classified according to the strength of the template-substrate interaction and according to the strength of the subsequent substrate-substrate bonding (Figure 1-3) [16]. Classical templates bind non-covalently to their substrates, and assist in the formation of covalent bonds. A closely related class includes templates like Feldman’s [32], top right in Figure 1-3 (discussed in Chapter 8); the only difference between this and the classical templates is the covalent nature of the bond between template and substrates. When the template is a linear chain, fully covalent systems of this type are called tethered reactions (see Chapters 6, 7, and 10). The tether brings groups into close proximity, thus enhancing reactivity. Many of the common reactions of organic synthesis can be viewed as examples of covalent/covalent templating. For example, in Scheme 1-7,the boron atom holds the three alkyl groups together so that they can bond to the carbon of potassium cyanide [33]. The Fischer indole synthesis is another classical example. The other examples shown in Figure 1-3 involve the template induced formation of non-covalent bonds; this type of process is best described as self-assembly. For example, in Mutter’s artificial proteins, several amphiphilic helices are covalently attached to a template, so determining the folding topology of the final globular structure [34]. The self-assembly of surface monolayers is another good example: when aliphatic carboxylic acids form monolayers on a water surface, or long-chain thiols self-assemble on gold,

1.3 Roles of Templates

covalent

nontovalent

9

-

Strength of Llgand-Template interaction

Figure 1-3 Templating and self-assembly.

()2YL(y;u

P

1) KCN

2) (CF3CO)zO 3) H202.NaOH

25

Scheme 1-7 Boron acts as a template, holding the three alkyl groups together, facilitating the reaction with the carbon atom of potassium cyanide.

the surface holds the alkyl chains in the correct orientation for optimal van der Waals interaction between the hydrocarbon chains [35].A non-covalent interaction between the template and the substrates induces a second non-covalent interaction. These examples show the close relationship between templating and self-assembly [36]. The emphasis of this book is on the use of templates for creating covalent bonds.

1.3.3 Topology of Reaction Templates can be categorized as “cyclization”, “linear”, or “interweaving”, according to their topology of operation, as shown in Figure 1-4 [16].

10

-

I Templates in Organic Synthesis: Definitions and Roles

Cyclisation

Linear

Interweaving

I

Figure 1-4 Classification of templates according to their topology of operation.

1.3.3.1 Cyclization templates The simplest type of template directed cyclization is metal cation induced macrocyclization, as discussed in Section 1.1. Mandolini and co-workers [37] have made a detailed study of the influence of alkali and alkaline earth metal cations on the cyclization of 2-hydroxyphenyl-3,6,9,12-tetraoxa-lCbromotetradecylether 28 in methanol and in dimethyl sulfoxide (Scheme 1-8). They studied different sizes of macrocycle and metal cation to determine the most effective combination for cyclization; the results from this study will be summarized in Section 1.4.2.3.

28.K'

29.K'

30.K+

Scheme 1-8 Metal cation template directed formation of benzo[ 18lcrown-6.

Macrocyclization templates are not restricted to metal cations but also include hydrophobic organic units, such as the adamantanecarboxylate templated formation of cage 24 described by Fujita (Scheme 1-6)[31]. Other examples, which will be described in later chapters, include Cram and co-workers' use of solvents to template formation of carceplexes: solvents such as dimethylacetamide were found to stabilize the charged intermediate formed during carceplex synthesis. The empty carcerands were never formed

1.3 Roles of Temulates

11

because this would require the intermediate to be unsolvated [38]. Organic charge transfer and n-n interactions have also been used in template directed synthesis, as in the preparation of Stoddart's [39a-c] macrocycle 35 (Scheme 1-9) (see Chapter 3). The initial dication 31 reacts with one end of the 1,4-bis(bromomethyl)benzene 32 to yield a tricationic intermediate 34. a- n Interactions between the electron-deficient 4,4 [bipyridinium unit and the electron rich hydroquinone of the template 33, and hydrogen bonding between the polyether chains of the template and CH2 groups in 34, result in rapid formation of a 1 :1 complex. The complex induces the reactive ends of the trication to come into close proximity, enhancing intramolecular coupling [39b]. The template can be removed by solvent extraction, providing an efficient route to the free cyclophane 35. This system has been extended to achieve the templated synthesis of catenanes and rotaxanes, as will be mentioned later.

3PFf

Br

32

J

0

34.33

0

4PFs

HO'

Scheme 1-9 The electron-rich hydroquinone 33 acts as template for the formation of tetracationic macrocycle 35.

Metal coordination also enables organic ligands to be used as templates. Sanders and co-workers have synthesized cyclic porphyrin oligomers using Glaser-Hay coupling [16,40]. This reaction oxidatively combines two terminal acetylenes to give a 1,3-butadiyne link. The syntheses of cyclic porphyrin dimer 38 and trimer 39 were effectively templated by 4,4'-bipyridine 37 and tripyridyltriazine 22, respectively (Scheme 1- 10).

12

1 Templates in Organic Synthesis: Definitions and Roles R

H

R

R

36

H

R

38.37 (72%)

R = CH2CH2COOMe

39.22 (52 %)

Scheme 1-10 Template directed synthesis of cyclic porphyrin dimer 38 and cyclic porphyrin trimer 39.

Scheme 1-11 Tetrapyridylporphyrin 42 templated formation of cyclic porphyrin tetramer 43.

14

I Templutes in Orgunic Synthesis: Definitions and Roles

The first step in both templated reactions is the combination of two porphyrin units 36 to yield a linear porphyrin dimer 40. This linear dimer binds the 4,4’-bipyridine 37 template and adopts a conformation in which intramolecular cyclization is strongly favored. Conversely, when the tridentate ligand 22 binds the linear dimer, it forces it into a conformation in which cyclization is disfavored; the linear dimer then undergoes intermolecular reaction to yield linear trimer, which cyclizes to cyclic trimer 39. The tridentate ligand 22 performs a largely preventative, negative, role in this trimer synthesis, by inhibiting linear dimer from cyclizing - it seems to be slightly too small to enhance cyclization of the linear trimer. The oligopyridine templates can be easily removed from these cyclic porphyrin oligomers by treatment with acid. Tetrapyridylporphyrin 42 templates the cyclization of linear porphyrin tetramer 41 and also the conversion of linear dimer 40 to cyclic tetramer 43 (Scheme 1- 11). In this latter case, the template binds the linear tetramer formed in the reaction, inducing a conformation favoring cyclization. If the porphyrins are converted to dioxoporphyrins [41], or ruthenium(I1)carbonyl porphyrins [42], the specificity of the templates is increased because the binding becomes stronger: the monomeric dioxoporphyrins preassemble around the templates before coupling. In the case of the ruthenium porphyrins it is less clear whether the mechanism is one of preassembly followed by coupling or coupling followed by strong binding of linear intermediates in favorable conformations for intramolecular cyclization. The preassembly route is not significant with zinc porphyrins because the stability constant for the porphyrin monomer-pyridine complex is too low. The drawback of strong binding in the case of dioxo and ruthenium porphyrins is that the template is so strongly bound by the product that the free macrocycle cannot readily be released. 1.3.3.2

Linear templates

Linear templates enhance reaction between two bound substrates rather than between two ends of the same substrate. The classical examples of this type of templating are replication of DNA and synthesis of RNA. In both cases, a single strand of DNA acts as a template, the base sequence on the template strand being complementary to the sequence produced on the new strand. The use of an oligonucleotide to template the formation of an imine, by Lynn and co-workers [30], has already been mentioned (Section 1.3.1, Scheme 1-5). One of the first examples of a non-nucleotide based organic linear template was developed by Kelly et al. [43]. The template 44 binds the two substrate molecules in a transient ternary complex 45.44.46, enhancing the bimolecular reaction (Scheme 1-12). Following on from this system, Kelly developed a template with two different binding sites so that inactive ternary complexes, where two of the same substrates bind to the template, are disfavored. Thus the effectiveness of the template was enhanced. Mock et al. [44] have shown that cucurbituril48 catalyzes the 1,3-dipolar cycloaddition shown in Scheme 1-13. Here, cucurbituril acts as a linear template; note that “linear” refers to the reaction topology and not to the shape of the template. 49 and 50 bind inside the cavity of 48 by hydrogen bonding between the ammonium groups and the rims of the cucurbituril. The reaction between 49 and 50 is made faster and more regiospecific; clean formation of 51 occurs.

1.3 Roles of Templates

15

Ph

Scheme 1-12 The template 44 simultaneously binds two substrates (45 and 46) in a ternary complex, acceleratingreaction between them.

0

v

-

0

48 50

51

Scheme 1-13 Cucurbituril catalyzed regiospecific formation of 51 in aqueous formic acid.

Diels-Alder reactions have also been accelerated inside the cavities of cyclic porphyrin trimers [45]. For example, diene 52 and dienophile 53 react selectively to give the e m adduct 54 (Scheme 1-14) inside the cavity of 39 [45a,b]. Cyclic porphyrin trimer 39 is an effective kinetic and thermodynamic template for this reversible Diels -Alder reaction, of which the stereochemical outcome may be reversed to give mainly the endo adduct if a smaller porphyrin trimer is used [45c]. Linear templates have potential for self-replication, since in principle the product can be identical to the template. Non-enzymic replication has been achieved with both nucleotide [46] and non-nucleotide [47] model systems. Scheme 1- 15 outlines one of the first

16

1 Templates in Organic Synthesis: Definitions and Roles

W- --# -\ - i /

39

Scheme 1-14 Inside the porphyrin trimer 39 cavity, diene 52 and dienophile 53 react selectively to give the ex0 adduct 54. The smaller version of trimer 39, with two butadiyne links replaced with ethyne units, templates the reaction with the opposite stereochemistry, to give the endo isomer of 54.

1.3 Roles of Templates

17

K = 60 M-'

simple bimolecular reaction pathway

product tempbated pathway

Scheme 1-15 Self-replicating system designed by Rebek and co-workers. The template 57 (X = OC6F,) binds to the two substrates 55 and 56, generating a ternary complex 55.57.56.Then 55 and 56 react to generate another molecule of template 57. Stability constants are shown for the 55.56 and 57.57 complexes.

18

1 Templates in Organic Synthesis: Definitions and Roles

self-replicating system designed by Rebek, based on Kemp’s triacid. The template 57 binds to the two substrates 55 and 56 generating a ternary complex 55.57.56. Reaction between these template bound substrates is favored over reaction in free solution, to yield the dimerized template 57.57. When the product dimer dissociates, two template molecules are released for further reaction. The reaction is autocatalytic; seeding the reaction mixture with its product leads to the expected rate enhancement. The initial rates of reaction are proportional to the square root of the product concentration. This “square root law”, identified by von Kiedrowski [48] to characterize nucleic acid replicators, applies because the template exists largely as its dimer and only a very small amount is bound to two different substrates as the ternary complex ready for reaction. By changing the naphthalene unit for a biphenyl, the rate of product formation via the ternary complex may be increased. In Section 1.4.2.1, the efficiency of the system illustrated in Scheme 1-15 is quantified in terms of effective molarity. Template 57 may also be formed by a competing route: substrate 55 may bind to substrate 56 to form a bimolecular complex 55.56 which also brings the reactive groups into close proximity.

1.3.3.3 Interweaving templates An interweaving template forces the substrates to form an interwoven topology; covalent modification locks this information permanently within the molecule - two or more rings being interlocked. Sauvage and co-workers’ contributions to the templated synthesis of catenanes and knots have been described in excellent reviews [49]. His group and others have used Cu’ as a template to place phenanthroline ligands in an orthogonal arrangement around the metal. On the addition of a linking agent, the catenate is formed in good yield. The strategy can be extended to the synthesis of a trefoil knot 60.60 (Scheme 1-16).A thread containing two phenanthroline units can wrap around two Cu’ centers to yield a double helix. If the linking group can be persuaded to react with the correct ends, then a trefoil knot will form. This is not the only product, but the fact that even 3% of the trefoil knot forms is amazing. The copper ion can be removed with potassium cyanide to yield the metal-free product. Here the template provides topological information but it does not accelerate covalent bond formation; an interweaving template does not necessarily act as a cyclization template. The templates used by Stoddart [39a, b,c] in the syntheses of catenanes and rotaxanes use n-n interactions to enhance both cyclization and interweaving. The template directed cyclization (Scheme 1-9) results in rotaxane formation if the ends of the template 33 are made so bulky that it cannot escape from the macrocycle, and in catenane formation if the two ends of the template are joined to form a macrocycle interlocked with the new macrocycle. The template is an integral part of the final product [39a,d]. Cucurbituril48 can act as both a linear template and a topological template in the formation of rotaxane, as discussed later (Scheme 1-20).

1.3 Roles of Templates

19

trefoil knot 60.60

Scheme 1-16 Copper(1) as an interweaving template in the synthesis of a trefoil knot.

1.3.4 Scavenger Templates Sanders and co-workers have shown that cyclization templates can be used to scavenge cyclizable material in a reaction mixture and thus facilitate the formation of linear oligomers [16, 501. Consider the general Scheme 1-17. The aim of this reaction is to prepare product D. Dimerization of the partially deprotected intermediate B can only be carried out efficiently in the absence of fully deprotected molecules C, because the latter can couple with mono-deprotected material B to generate a new reactive oligomer and thus give a complex mixture. Conventionally, this problem is avoided by isolation and purification of B before coupling, but separation becomes increasingly difficult with longer chains. Scavenger templates overcome this problem by enforcing intramolecular

20

1 Templates in Organic Synthesis: Definitions and Roles

reaction of doubly reactive molecules C; mono-reactive molecules B have no choice but to couple to each other to give D. The separation may be postponed until after coupling, when it becomes easier because the desired linear compound D is twice as massive as either the starting material A or the cyclic by-product E. The template does not promote the formation of the longer oligomer directly. This method has facilitated the preparation of a linear porphyrin octamer [50].

Scheme 1-17 A scavenger template induces molecules with two reactive ends to cyclize, so allowing efficient coupling of mono-protected material. The open circles represent protecting groups.

1.3.5 Negative Templates The templates discussed so far favor reaction between bound substrates; they are positive templates. When a template disfavors reaction between bound substrates, it is called a “negative template” [ 16,40,50] (Scheme 1-18). A negative template disfavors the formation of a given product not by accelerating a competitive reaction but by specifically disfavoring the particular spatial ordering of atoms which would give that product. It holds the substrate in the wrong geometry for reaction; in Scheme 1-18 the negative template acts as a straitjacket, preventing the substrate from cyclizing. In ideal cases, the negative template may also have a dual role as a positive template in a subsequent step, or in an alternative reaction. In principle, any system which can be induced to adopt a particular conformation by a positive template can be prevented from doing so by a negative template. Negative templating of undesirable reactions is beneficial in systems which are under kinetic control, since there are many pathways down which such a reaction can proceed, only one of which leads to the desired product. A good example of negative templating is described by Sanders and co-workers [40, 501 (Scheme 1-1 1). The linear porphyrin dimer 40 can be prevented from cyclizing to cyclic dimer 38 by tetrapyridylporphyrin 42. In the sec-

1.4 Measuring Template Effects

k:

1

negative

positive template

\

~

21

intermolecular coupling

=

intramolecular coupling

Scheme 1-18 Schematic illustration of positive and negative templating.

ond step, the template acts positively and cyclizes linear porphyrin tetramer 41 to cyclic tetramer 43.

1.4 Measuring Template Effects 1.4.1 Qualitative Detection of Template Effects Kinetic templates can be evaluated by measuring rates of reaction, but it is easier to analyze their effect on the yield of product. The practical test for a “template effect” is to see whether the template increases the yield. If the yield is unaffected by the template, this implies that the template is the wrong shape, or that substrate-template binding is too weak under the chosen conditions, or that the reaction conditions are too concentrated so that the substrate proximity induced by the template is insignificant, or that there are so few competing reactions that the template has no effect on the product distribution. If the yield of product is enhanced by the template, it is still necessary to demonstrate that the template is binding to, and controlling the spatial arrangement of, the starting materials or intermediates, rather than acting as a conventional catalyst or reagent. In cyclizations, the main competing reaction which is reduced by the template is intermolecular coupling, giving linear oligomers, large rings, and polymers. In linear coupling reactions there is no built-in competition of this type, so it can be difficult to determine whether a linear template is operational without measuring rates: the product may be the same whether it is formed on the template or not. Sanders and co-workers have used a competition experiment to overcome this problem [40], enabling quantitative and qualitative information about linear template efficiency to be obtained, as outlined in Scheme 1- 19. There are two different types of substrate: those which can bind to the template (shown in black) and those that cannot (shown in white). With an ideal template, all the substrate capable of binding to the template would bind and react quickly,

22

1 Templates in Organic Synthesis: Definitions and Roles

(a) 4

.

1

statistical coupling

+ .

4u

+ +

ternplated coupling

Scheme 1-19 (a) Statistical reaction and (b) coupling in the presence of a linear template,

leaving the unbound substrate in free solution to react more slowly (Scheme 1-19b). Thus, by comparing the product distributions with and without the template, it is possible to determine whether there is a template effect. In general, product distribution analysis is only used to provide qualitative evidence for template effects. In the next section, we will discuss the parameters which are important in the quantification of template effects and show how choice of concentration regime can be used to optimize the effectiveness of a template.

1.4.2 Quantification of Kinetic Template Effects in Terms of Effective Molarity, Substrate Affinity, and Maximum Rate Enhancement Kinetic templates accelerate reaction of bound substrates, which makes it tempting to quantify template effects in terms of “rate enhancement”. In this section, we will show how this can be misleading because such rate enhancements are concentration dependent. We will elucidate the parameters which determine the rate enhancement achieved with a kinetic template, by analyzing the thermodynamic and kinetic behavior of simple theoretical models, and applying these models to published template systems. Our theoretical models are similar to the Michaelis-Menten analysis of enzyme catalyzed reactions [5 11, except that we assume there is no catalytic turnover. First, we consider linear templates, then cyclization templates. In general, the rate of reaction varies as the reaction proceeds; whenever we refer to rates in the following discussion, we mean initial rates.

1.4 Measuring Template Effects

23

1.4.2.1 Linear templates Consider the situation where two molecules of a substrate S, of initial concentration [S],, react together to yield a product P:

The bimolecular rate constant for the unternplated reaction is k2,so the initial rate of the reaction in the absence of a template is: 2

RQteUnternp = k2 [SI0

(1 -2)

The reaction is facilitated by a linear template T. We will assume that this template has two independent, identical, binding sites; both bind substrates with the same microscopic binding constant K, to give a binary complex S - Tand a ternary complex S.T.S.

S+T

2K + S-T

The concentrations of unbound substrate [S] and unbound template [TI are related to the concentration of these complexes by the equilibrium constant.

2 K = [S*T]/([S][TI)

(1-5)

K2 = [S.T*S]/([S]2[T])

(1-6)

If the total concentration of template is half the total concentration of substrate (i.e., [S], = 2[T],), then the concentrations of S, S.T, and S . T . Svary with [S],, as illustrated by curves (a), (b), and (c), respectively, in Figure 1-5 (calculated for the arbitrary value K = lo3 M-I). The termolecular complex S.T.S becomes the main species in solution when [S], %- 1/K. The unimolecular rate constant for conversion of the ternary complex S .T.S to the template product T.P is k l .

S0T.S

k

T-P

(1-7)

So the initial rate of intramolecular reaction within the termolecular S .T .S complex is: Ratel,, = k,[S.T-S]= K2kl[S]2[T]

(1-8)

Let us assume that when a substrate molecule binds a template, this has no effect on the rate of intermolecular reaction of that substrate with other free substrates, or with sub-

24

1 Templates in Organic Synthesis: Definitions and Roles

1500

g

z

:

[Sla = 344K)

1000~

2

6 22 d

500-

(9)

/

-0' 0-

/

-1

*

c- Max Rate Enhancement = 1 + 2EM W27

\ \ L.

---

1

Figure 1-5 Curves (a)-(g) show how [S], [ST],[S.T.S], RateTemp,Rareuntemp,Rate,,,,, and Rate Enhancement vary with [S],. Note that concentrations and rates have been normalized by dividing by [S],, and that rates are initial rates. (The following are arbitrarily assumed: [S], = 2[T],, K = lo3 M-', k , = 10 s-I, and k2 = 1 s-' M-'; see Appendix l a for details of these curves.)

1.4 Measuring Template Effects

25

strates bound to other templates. So the template has no effect on the rate of intermolecular reaction, and the rate of reaction in the presence of the template is:

Rate~emp= Rateuntemp + Ratelntra

(1 -9)

RateTemp(d), RateUntemp(e) and Ratelntra(f) are plotted as functions of [S], in Figure 1-5 (assuming k , = 10 s-l and k2 = 1 s-’ M-’).The rate of the reaction in the absence of template (e) increases very steeply with concentration, because it is bimolecular, whereas the rate of reaction via S . T .S (f) levels off where [S], % 1/K, when all of the substrate is bound, and is asymptotic with a limiting value of [SIok,/2. There is a certain value of [S], at which the reaction in the absence of template (e) becomes greater than the maximum possible rate of reaction in the ternary complex (i.e., when k2[SIO> k,/2).When [S],= k , / ( 2 k 2 ) ,the presence of the template simply doubles the overall rate of reaction (d) and as [S], increases above this value, the effect of the template becomes insignificant. The critical concentration k,/k2is a key quantity for defining the effectiveness of a template and it is known as the “effective molarity” of the system, EM [52]. EM = kl/kz

(1-10)

When [S], = EM/2, the termolecular complex S . T - S undergoes intermolecular and intramolecular reaction at equal rates. The factor of 2 results from the fact that we have a reaction between two identical substrate molecules. Now let us see how the rate enhancement varies with [S],.The rate enhancement can be defined as the ratio of the initial rates of reaction in the presence and absence of the template, which gives:

Rate Enhancement =

RateTemp

Rateunternp

=1+

EMK2[SI4 2[SIi

(1-11)

The rate enhancement, plotted as a function of [S], in Figure 1-5 (g), reaches a maximum value of 1 + 2 E M . K / 2 7 when [S],= 3 / ( 4 K )(these are exact algebraic results, independent of the values of k,,k,, and K). Curve (g) shows that it is misleading to state a rate enhancement for a linear template at some arbitrary concentration [S],.The maximum rate enhancement occurs when the rates of the templated and untemplated reactions are both low; the intermolecular reaction is barely perceptible whereas the reaction in the ternary complex is proceeding several orders of magnitude faster; the observed rate enhancement is therefore very high. From inspection of the curves in Figure 1-5, it is clear that there are two important parameters which need to be determined in order to evaluate a linear template system: the binding constant K and the effective molarity EM. At concentrations significantly lower than 3 / ( 4 K ) , there will be very little of the ternary complex S . T - Spresent and so

26

I Templates in Organic Synthesis: Definitions and Roles

the template directed reaction will be insignificant. At concentrations higher than 3/(4K), intermolecular reaction starts to compete, even if the substrates are bound on a template in close proximity. It is interesting to note that the optimum concentration depends only on the binding constant K, whereas the magnitude of the peak rate enhancement depends on the product of the binding constant and the effective molarity. Values of EM and K for five real linear template systems are compared in Figures 1-6- 1-9 and Scheme 1-20. Effective molarities usually combine the uncertainties from a number of experimental binding constants and rate constants, so the values quoted here should be regarded as order of magnitude estimates. The situation which most resembles our theoretical model is that shown in Figure 1-6 [40], because the tetrapyridylporphyrin template 42 has two identical, essentially independent, binding sites for the linear dimer substrate 61. Although the effective molarity of this system is low (EM = 5 x M), this corresponds to a respectable calculated maximum rate enhancement because the binding constant K is so high. Note that if this reaction had been studied at concentrations higher than M, no template effect would have been observed. The cyclic porphyrin trimer templated Diels-Alder reaction [45] (Figure 1-7) also fits reasonably well to our simple model because the binding sites are equivalent and independent; although

EM- .5x104M

K = 3 x 10' M-'

Max Rate Enhancement= 100

Figure 1-6 Template efficiency parameters for the tetrapyridylporphyrin templated Glaser coupling of two zinc porphyrin dimers, in dichloromethane.

1.4 Measuring Template Effects

27

52.39.53

EM= 4 M K = 350 M-'

- -

Max Rate Enhancement = 100

Figure 1-7 Parameters for the porphyrin trimer templated e m Diels-Alder reaction, in 1,1,2,2tetrachloroethane at 60 "C (cf. Scheme 1-14).

EMm3M

K = 60 M-'

0 x 0

5547.56

Figure 1-8 Effective molarity and stability constant for the ternary complex in Rebek's self-replicator (cf. Scheme 1-15).

there are two substrates (52 and 53), they have similar binding constants (500 M - ~and 250 M - ~respectively at 60 "C).The effective molarity is about 4 M, corresponding to a rate enhancement similar to that in the tetrapyridylporphyrin templated reaction. The rate enhancement becomes higher at lower temperatures (30 "C), due to increased binding, as expected from Equation (1-11). The cucurbituril templated cycloaddition (Scheme 1-20) has a much higher effective molarity (EM = 4 x lo4 M). This pair of substrates was chosen for detailed kinetic analysis, rather than 49 and 50 (Scheme 1-13) because in this case catalytic turnover is prevented, because the product 48.64 is a rotaxane [44]. The substrates 62 and 63 have fairly similar affinities for the template (2.3 x lo3 M-' and ca. 7.9 x lo2 M-' respectively), but binding at the two sites shows a strong negative cooperativity. The stability constant of the ternary complex 62.48.63 is only 2.4 x lo4 M - ~ ;for

28

1 Templutes in Orgunic Synthesis: Dejinitions and Roles

Figure 1-9 Effective molarity and stability constant for a hexadeoxynucleotide template at 0 "C.

62

+ ____t

48

48.64 (rotaxane) EM- 4 x lo4 M K - 150M-' Max Rate Enhancement = 4 x lo5

Scheme 1-20 Parameters for cucurbituril48 acting as linear and topological templates.

1.4 Meusuring Templute Effects

29

our analysis, we need to take an effective binding constant, K , which is the square root of this, giving a maximum rate enhancement of 4 x lo5. The kinetic analysis of a self-replicating system is complicated because of template dimerization, so it is difficult to estimate maximum rate enhancements for these systems. However, we can still compare the effective molarities and binding constants of self-replicating linear templates, as illustrated by Figures 1-8 [47d] and 1-9. The substrate binding constant of von Kiedrowski’s hexadeoxynucleotide template [46b] (Figure 1-9) has not been measured but can be estimated to be ca. 900 M-’ under the reaction conditions using the nearest-neighbor parameters for predicting DNA duplex stability [53].

1.4.2.2 Quantitative analysis of template effects in tethered reactions Tethered reactions can be regarded as linear templated systems in which the templatesubstrate binding is infinitely strong. The “template efficiency” is therefore defined simply by the effective molarity for the intramolecular reaction; the rate enhancement becomes greater than 2 when [S], < EM, and becomes infinite at infinite dilution.

1.4.2.3 Cyclization templates The kinetics of templated cyclization reactions can be considered in the same way as for the linear coupling described in Section 1.4.2.1. There is one significant difference: cyclization reactions are intramolecular, so they have characteristic effective molarities even in the absence of a template. Consider a substrate S which can cyclize intramolecularly to a give a product P or react intermolecularly to give a linear dimer D (which can go on to give longer linear and cyclic oligomers).

S

L

S+S

P

%

(1-12)

D

(1-13)

In the absence of a template, the initial rates of untemplated cyclization (Rateuntempcyc) and intermolecular coupling (Rate,) are: Rateuntempcyc = kl PI,

(1-14)

Rate, = k2[S]g

(1-15)

The substrate can bind a template T, with binding constant K , to form a complex S . T which cyclizes more rapidly.

S+T

K

S.T

(1-16)

30

I Templates in Organic Synthesis: Definitions and Roles

The rate of cyclization of the substrate, when bound to the template, RuleTempCyc, is given by Equation (1-19), where k3 is the unimolecular rate constant for substrate cyclization in the presence of the template.

S.T

-%

P.T

(1-18)

EM,, is the effective molarity for the cyclization of the substrate bound to the template and EMuntempis the effective molarity for the cyclization of the free substrate. EMuntempindicates the inherent tendency of the substrate to cyclize. EMTemp = k3/k2

( 1-20)

(1-21)

If we assume that template binding has no effect on the rate of intermolecular coupling (as we assumed for linear templates), then the overall initial rate of product formation in the presence of the template is:

This allows the following expression to be derived for the Rate Enhancement: (1-23)

- [s] EMTempK[S12 -tS10 EMuntemp [SIO +

(1 -24)

In Figure 1-10, curve (h) shows how the rate enhancement varies as a function of [Slo (for [S], = [TI,, K = lo3 M-', EM,,,, = 0.1 M and EMuntemp= lo4 M). Rate Enhancement is concentration dependent and is therefore a misleading quantity unless the concentration at which it is measured is quoted together with the binding constant K . At high concentrations, when the substrate is all bound to the template, the rate enhancement when [S], < 1/K, tends towards the ratio of the effective molarities EMTemp/EMUntemp; the Rate Enhancement tends towards unity (no effect) because there is no binding. Curve (i) shows the fraction of S which cyclizes in the absence of template and curve (j) the fraction of S which cyclizes in the presence of the template; at low concentrations the inherent tendency of the substrate to cyclize means that the fraction cyclizing approaches unity, whereas at high concentrations, intermolecular reaction competes with cyclization. Subtraction of curve (i) from (j)results in curve (k) which illustrates the concentration regime over which the template is effective, which is EMuntemp< [ S ] , < EM,,.

1.4 Measuring Template Effects

31

p-

10000

100

.

untemplated reaction

50

I

%, ,

,

dnplated ction ~

~

0 1.0 1

a, - (1) 0.5

0.0

J. '

-6

-5

-4

-3

-2

-1

0

1

lo€"

Figure 1-10 Curve (h) shows the variation in the Rate Enhancement with respect to log [ S ] , (for K = lo3 M-', EMTemp= 0.1 M and EMUntemp = M). Curve (i) shows the fraction of S which cyclizes in the absence of template and curve (j)the fraction of S which cyclizes in the presence of the template. Subtraction of curve (i) from 6)results in curve (k). (See Appendix l b for details.)

32

1 Templates in Organic Synthesis: Definitions and Roles H 414 2

0.0009M EM"ntmp- 0.00015M K = 2 x lo6M-'

ffimp= 0.001 M H

EMunsmp0.0005M

0.0003M 0.00015M

K - 7 x IO'M-'

Figure 1-11 Effective molarities and binding constants for cyclization of linear porphyrin oligomers, by Glaser coupling in dichloromethane.

1.5 Conclusion

33

At concentrations higher than EMTemp,intermolecular reaction is favored even in the presence of template, and at concentrations lower than EMuntemp the substrate cyclizes so efficiently that the template has little effect. Table 1- 1 provides some examples of cyclization effective molaritjes for the formation of benzocrown ethers in the presence of a variety of group I metal cation templates [37a,b]. The highest effective molarity in this series is achieved by the potassium cation when it templates the formation of benzo-18-crown-6 (y = 5 , Scheme 1-8); here the EMTem, of 123 M is 1500 times higher than EMunlemp. Figure 1-11 gives effective molarities for the cyclization of some linear porphyrh oligomers by Glaser coupling [40]. These effective molarities are all very low but cyclization is significantly favored by the template and the strong binding constants enable coupling to be carried out efficiently at very low concentration.

Table 1-1 Effective molarities (M) for various metal cations used as templates for the cyclization of 68 ( y = 3, 4,5,6,9, and 15) in Me,SO at 25 "C.

Y

3 4 5

6 9

15

Na+

K+

Rb+

cs+

1.8 26

1 10 123 8 0.9 0.1

0.7 6 48 20 2.1

4 22 25

14 0.5 0.1

0.04

0.2

0.6

1.2 0.2

0.08

0.09 0.08 0.07 0.04

0.02

1.5 Conclusion This chapter illustrates how templates have been used to aid organic synthesis and attempts to refine and expand the definition of a molecular template. The later chapters in this book demonstrate that templates are emerging as powerful tools in many areas of molecular construction. We have highlighted the key parameters required to evaluate template effects quantitatively. We hope this will encourage pioneers in the field to calibrate new systems, so that we can gauge their progress as they escalate to higher levels of efficiency and sophistication.

34

I Templates in Organic Synthesis: Definitions and Roles

Appendix 1 a: Equations for Figure 1-5 IS], = [S] + [S.T] + 2[S*T.S]

( 1-25)

[TIo= [TI + [S.T]+ [S.T.S]

( 1-26)

Combination of mass balance Equations (I -25) and (1 -26) with the thermodynamic Equations (1-5) and (1 -6) gives Equations (1-27), (1 -28), and (1-29).These functions are illustrated in Figure 1-5 (a) to (c). (a) [Sl

=

-1

+ ,!I+ I----

4K[S]"

2K

( 1-27)

(b) [S*T] = (2K[S13)/[S]i

( 1-28)

(c) [S-T-S]= (K2[S]4)/[S]i

(1 -29)

From Equations (1-9) and (1-30), Equations (1-31), (1-2), and (1-32) for RateTempr Rateuntemp,and Ratelntracan be obtained. These functions are illustrated in Figure 1-5 (d) to (g). (1-31)

(1-32) Figure 1-5 (g) shows the concentration dependence of the Rate Enhancement.

+ EMK2[SI4

(g) Rate Enhancement = 1

2rs1;

(1-11)

Appendix 1 b: Equations for Figure 1-10 (1-33) ( 1-34)

References

35

Combination of mass balance Equations (1-33) and (1-34) with the thermodynamic Equation (1-17) gives: -~

[SI =

-1+ ,'1+4K[S]"

(1-35)

2K

The functions (1-24), (1-36), and (1-37) are illustrated in Figure 1-10 (h) to (j).They describe the concentration dependence of the effectiveness of a cyclization template. (h) Rate Enhancement

-

RateTemp RateUntempCyc

( 1-23)

(1 -24)

(1-36)

References [l] (a) J. Turner (Ed.), The Dictionary ofArt, Macmillan, London, 1996, Vof. 30; (b) F. S. Merritt (Ed.), Building Design and Construction Handbook, 4th edn., McGraw-Hill, New York, 1982. [2] A. Didron, Ann. Archkol. 1845,2, 150. [3] (a) F. B. Andrews, The Mediaeval Builder and His Methods, Barnes and Noble, New York, 1993; (b) L. F. Salzman, Building in England Down to 1540: a Documentary History, Oxford University Press, Oxford, 1952. [4] J. D. Watson, F. H. C. Crick, Nature (London) 1953, 171, 737-738. [5] A. R. Todd (Ed.), Perspectives in Organic Chemistry; Interscience, London, 1956, p. 263. [6] F. Seidel, Chem. Ber: 1926,59B, 1894- 1908. This reaction had been previously investigated by T. Posner, Berichte 1898, 656-660, but from the limited characterization data it seems that the macrocycle 2 was not formed, maybe because the reaction mixture contained water.

36

I Templates iti Organic Synthesis: Definitions and Roles

171 (a) G. A. Melson, D. H. Busch, Proc. Chem. Soc., London, 1963,223-224: (b) D. H. Busch, Rec. Chem. Prog. 1964,25, 106- 126. [8] (a) R. P. Linstead, J . Chem. Soc. 1934, 1016-1017; (b) G. T. Byme, R. P. Linstead, A. R. Lowe, J . Chem. Soc. 1934, 1017-1022. (91 N. F. Curtis, Coord. Chem. Rev. 1968,3,3-47. [lo] (a) N. F. Curtis, R. W. Hay, J . Chem. SOC.,Chem. Commun. 1966,524-525; (b) N. F. Curtis, D. A. House, Chem. lnd. 1961,1708-1709. [1 1 ] C. J. Pedersen, Angew. Chem., fnr. Ed. Engl. 1988,27, 102 1 - 1027. [ 121 (a) D. H. Busch, J. A. Burke Jr., D. C. Jicha, M. C. Thompson, M. L. Morris, Adv. Chem. %r. 1962, 37, 125-142; (b) Chem. Eng. News 1962, 40, 57; (c) D. H. Busch, Adv. Chern. Ser. 1963,37,1- 18. [I31 (a) M. C. Thompson, D. H. Busch, J . Am. Chem. Sac. 1962, 84, 1762-1763; (b) M. C. Thompson, D. H. Busch, J. Am. Chem. SOC.1964,86,3651-3656. [I41 D. H. Busch, A. L. Vance, A. G. Kolchinksii, in Comprehensive Supramolecular Chemistry, Val. 9, Eds.: J.-P. Sauvage, M. W. Hosseini, Elsevier, Oxford, 1996, pp. 1-42. 1151 R. Hoss, F. Vogtle,Angew. Chem., lnt. Ed. Engl. 1994,33,375-384. [16] S. Anderson, H. L. Anderson, J. K. M. Sanders, Acc. Chem. Res. 1993,26,469-475. [I 71 J. F. Stoddart, in Frontiers in Supramolecular Organic Chemistry and Photochemistry, Eds.: H.-J. Schneider, H. Dun; VCH, Weinheim, 1991, pp. 251-263. [ 181 B. Dietrich, P. Viout, J.-M. Lehn, Macrocyclic Chemistry, VCH, Weinheim, 1993. [ 191 L. F. Lindoy, The Chemistry of Macrocyclic Ligand Complexes, Cambridge University Press, Cambridge, 1989. 1201 E. C. Constable, Metals and Ligand Reactivity, Ellis Horwood, Chichester, 1990. [21] (a) D. H. Busch, J . Inclusion Phenom. 1992, 12,389-395; (b) D. H. Busch, N. A. Stephenson, Coord. Chem. Rev. 1990,100, 119-154. 1221 (a) H. Gies, B. Marler, Zeolites 1992, 12, 42-49; (b) T. Loiseau, G. FCrey, J . Chem. Soc., Chem. Commun. 1992, 1197-1198. [23] J. S. Beck, J. C. Vartuli, W. J. Roth, M. E. Leonowicz, C. T. Kresge, K. D. Schmitt, C. T.-W. Chu, D. H. Olson, E. W. Sheppard, S. B. McCullen, J. B. Higgins, J. L. Schlenker, J . Am. Chem. SOC.1992,114,10834-10843. [24] (a) C. T. Kresge, M. E. Leonowicz, W. J. Roth, J. C. Vartuli, J. S . Beck, Nature (London) 1992,359,710-712; (b) C. R. Martin,Acc. Chem. Res. 1995,28,61-68. 1251 Y. A. Vlasov, N. Yao, D. J. Norris, Adv. Muter. 1999, 11, 165-169. 1261 M. C. Thompson, D. H. Busch,J.Am. Chem. SOC.1964,86,213-217. 1271 (a) 3. D. Curry, D. H. Busch, J. Am. Chem. SOC.1964,86,592-594; (b) G. A. Melson, D. H. Busch,J.Am. Chem. SOC. 1965,87, 1706-1710. 1281 E. L. Blinn, D. H. Busch, fnorg. Chem. 1968, 7,820-824. [29] (a) A. Meller, A. Ossko, Monatsh. Chem. 1972, 103, 150- 155; (b) T. J. Marks, D. R. Stojakovic, J . Am. Chem. SOC. 1978, 100, 1695-1705; (c) M. Geyer, F. Plenzig, J. Rauschnabel, M. Hanack, B. del Ray, A. Sastre, T. Torres, Synthesis 1996, 1139-1151; (d) N. Kabayashi, R. Kondo, S. Nakajima, T. Osa, J . Am. Chem. SOC. 1990,112,9640-9641; (e) A. Weitemeyer, H. Kliesch, D. Wohrle, J. Org. Chem. 1995,60,4900-4904. 1301 (a) Z.-Y. J. Zhan, D. G . Lynn, J . Am. Chem. SOC. 1997,119, 12420-12421; (b) J. T. Goodwin, D. G. Lynn, J.Am. Chem. SOC. 1992,114,9197-9198; (c) P. Luo, J. C. Leitzel, Z.-Y. J. Zhan, D. G. Lynn, J . Am. Chem. SOC.1998,120,3019-3031; (d) J. T. Goodwin, P. Luo, J. C. Leitzel, D. G. Lynn, in Self-Production of Supramolecular Structures: From Synthetic Structures to Models of Minimal Living Systems, Eds.: G . R. Fleischaker, S. Colonna, P. L. Luisi, Kluwer Academic Publishers, Dordrecht, The Netherlands, 1994, pp. 99- 104.

References

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1311 (a) F. lbukuro, T. Kusukawa, M. Fujita, J . Am. Chem. SOC. 1998, 120, 8561-8562; (b) M. Fujita, Chem. Snc. Rev. 1998,417-425; (c) M. Fujita, Acc. Chem. Rex 1999,32, 53-61. [32] (a) K. S. Feldman, Y. B. Lee, J . Am, Chem. SOC.1987,109,5850-5851; (b) K. S. Feldman, J. S. Bobo, G. L. Tewalt, J. Org. Chem. 1992,57,4573-4574. [33] A. Pelter, M. G. Hutchings, K. Rowe, K. Smith, J . Chem. Soc., Perkin I 1975, 138-143. 1341 G. Tuchscherer, L. Scheibler, P. Dumy, M. Mutter, Biopolymers (Peptide Science) 1998,47, 63-73. [35] C. D. Bain, G. M. Whitesides, Angew. Chem., Int. Ed. Engl. 1989, 28, 506-512. [36) (a) J. S. Lindsey, New J . Chem. 1991, IS, 153-180; (b) G. M. Whitesides, J. P. Mathais, C. T. Seto, Science (Washington, DC) 1991, 254, 1312-1319; (c) D. Philp, J. F. Stoddart, Angew. Chem., Int. Ed. Engl. 1996,35, 1 154- 1196. [37] (a) G. Illuminati, L. Mandolini, B. Masci, J . Am. Chem. SOC.1983, 105, 555-563; (b) L. Mandolini, B. Masci, J. Am. Chem. SOC. 1984, 106, 168- 174; (c) R. Cacciapaglia, L. Mandolini, Chem. SOC.Rev. 1993,221 -231, [38] (a) D. J. Cram, J. M. Cram, Container Molecules and Their Guests, Royal Society of Chemistry, Cambridge, 1994; (b) J.A. Bryant, M. T. Blanda, M. Vincenti, D. J. Cram, J.Am. Chem. SOC. 1991,113,2167-2172. [39] (a) D. B. Amabilino, J. F. Stoddart, Chem. Rev. 1995,95,2725-2828; (b) S. Capobianchi, G . Doddi, G . Ercolani, J. W. Keyes, P. Mencarelli, J . Org. Chem. 1997,62,7015-7017; (c) D. B. Amabilino, P.-L. Anelli, P. R. Ashton, G. R. Brown, E. Cbrdova, L. A. Godinez, W. Hayes, A. E. Kaifer, D. Philp, A. M. Z. Slawin, N. Spencer, J. F. Stoddart, M. S. Tolley, D. J. Williams, J . Am. Chem. SOC.1995, I1 7, l 1142- l l 170; (d) D. G. Hamilton, J. E. Davies, L. Prodi, J. K. M. Sanders, Chem. Eur. J. 1998,4,608-620. [40] S. Anderson, H. L. Anderson, J. K. M. Sanders, J . Chem. Soc., Perkin I 1995, 22552267. [41] D. W. J. McCallien, J. K. M. Sanders, J . Am. Chem. SOC.1995, 117,6611-6612. [42] V. Marvaud, A. Vidal-Ferran, S . J. Webb, J. K. M. Sanders, J . Chem. Soc., Dalton Trans. 1997,985-990. [43] (a) T. R. Kelly, C. Zhao, G . J. Bridger, J. Am. Chem. SOC. 1989, 111, 3744-3745; (b) T. R. Kelly, G. J. Bridger, C. Zhao, J. Am. Chem. SOC.1990,112,8024-8034. [44] W. L. Mock, T. A. h a , J. P. Wepsiec, M. Adhya, J . Org. Chem. 1989,54,5302-5308. [45] (a) C. J. Walter, H. L. Anderson, J. K. M . Sanders, J. Chem. SOC.,Chem. Commun. 1993, 458-460; (b) C. J. Walter, J. K. M. Sanders, Angew. Chem., lnt. Ed. Engl. 1995, 34, 217219; (c) Z. Clyde-Watson, A. Vidal-Ferran, L. J. Twyman, C. J. Walter, D. W. J. McCallien, S. Fanni, N. Bampos, R. S . Wylie, J. K. M. Sanders, New. J . Chem. 1998,493-502; (d) M. Marty, Z . Clyde-Watson, L. J. Twyman, M. Nakash, J. K. M. Sanders, Chem. Commun. 1998, 2265-2266. [46] (a) L. E. Orgel, Acc. Chem. Res. 1995,28, 109- 118; (b) G. von Kiedrowski, Angew. Chem., Int. Ed. Engl. 1986,25,932-935; (c) D. Severs, G. von Kiedrowski, Chem. Eur. J . 1998,4, 629-641; (d) A. Luther, R. Brandsch, G . von Kiedrowski, Nature (London) 1998,396,245248; (e) T. Li, K. C. Nicolaou, Nature (London) 1994,369,218-221. [47] (a) D. H. Lee, J. R. Granja, J. A. Martinez, K. Severin, M. R. Ghadiri, Nature (London) 1996, 382,525-528; (b) K. Severin, D. H. Lee, J. A. Martinez, M. R. Ghadiri, Chem. Eur. J . 1997, 3, 1017-1024; (c) T. Tjivikua, P. Ballester, J. Rebek, Jr., J . Am. Chem. Soc., 1990, 112, 1249-1250; (d) J. S. Nowick, Q. Feng, T. Tjivikua, P. Ballester, J. Rebek, Jr., J . Am. Chem. Snc. 1991, 113, 8831-8839; (e) E. A. Wintner, M. M. Conn, J. Rebek, Jr., Acc. Chem. Res. 1994,27, 198-203; (f)E. A. Wintner, M. M. Conn, J. Rebek, Jr., J . Am. Chem. SOC.1994, 116, 8877-8884; (g) E. A. Wintner, J. Rebek, Jr., Acta Chem. Scand. 1996, 50, 467-485;

38

[48] [49]

[50]

[S11

[52] [53]

I Templates in Organic Synthesis: Definitions and Roles (h) A. Terfort, G. von Kiedrowski, Angew. Chem., Int. Ed. EngZ. 1992, 31, 654-656; ( i ) S. Yao, I. Ghosh, R. Zutshi, J. Chmielewski, Angew. Chem., Int. Ed. Engl. 1998,37,478-48 I . G. von Kiedrowski, Bioorg. Chem. Front. 1993,3, 11 3 - 146. (a) J.-P. Sauvage, Acc. Chem. Res. 1990, 23, 319-327; (b) J.-C. Chambron, C. 0. DietrichBuchecker, V. Heitz, J.-F. Nierengarten, J.-P. Sauvage, C. Pascard, J. Guilhem, Pure Apppl. Chem. 1995,67,233-240. (a) S. Anderson, H. L. Anderson, J. K. M. Sanders, Angew. Chem., Int. Ed. Engl. 1992, 31, 907-910; (b) S. Anderson, H. L. Anderson, J. K. M. Sanders, J . Chem. Soc., Perkin Trans. I 1995,2247-2254. A. R. Schulz, Enzyme Kinetics, Cambridge University Press, Cambridge, 1994. (a) A. J. Kirby, Adv. Phys. Org. Chem. 1980, 17, 183-278; (b) L. Mandolini, Adv. Phys. Org. Chem. 1986,22, 1-111; (c) M. I. Page, Chem. Soc. Rev. 1973,295-323; (d) K. A. Connors, Chemical Kinetics, VCH, New York, 1990,363-368. J. SantaLucia, Jr., H. T. Allawi, P. A. Seneviratne, Biochemistry 1996, 35, 3555-3562.

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

2 Templated Synthesis of Polymers - Molecularly Imprinted Materials for Recognition and Catalysis Giinter Wulff

2.1 Introduction Templates that are non-covalently or covalently attached to reacting substrates can control the reaction pathway with regard to the chemical composition and the stereochemistry of the products formed. Thus, in many cases it is possible to transfer properties of the template to the reaction product. Looking at this concept from the standpoint of a polymer chemist, at least four different cases can be distinguished: A low-molecular-weight template controls the synthesis of low-molecular-weight compounds. This principle is often used for the preparation of cyclic compounds, but many asymmetric syntheses also fall into this scheme. A polymeric template controls the outcome of a reaction of low-molecular-weight compounds. Enzyme-catalyzed reactions can be looked at in this manner. High-molecular-weight templates control the formation of macromolecules. Apart from the frequent examples in biochemistry ( e g,biosynthesis of nucleic acids, proteins, etc.), this is the case in the so-called “template polymerization” in which monomers are bound to a polymer that acts as a template to give, after polymerization and removal of the template, defined linear polymers [ 1,2]. In this review article, templated syntheses of macromolecules and polymeric materials will be discussed in which a low-molecular-weight template controls the structure of macromolecules. The composition (e.g., the proportion of co-monomers), the sequence of co-monomers as well as the stereochemistry (including the chirality) of the newly formed stereogenic centers is controlled during the polymerization of double bonds. The general idea of the research work presented here focuses on attempts to control the constitution and the configuration of complex supramolecular arrangements by specific interactions of the constituents with a suitable template molecule [3]. If in this case the constituents bear polymerizable groups, the whole constituent-template complex can be polymerized and, thus, the original structure will be stabilized and frozen. After removal of the template molecules, polymers with defined structures are obtained by transfer of structural information from template to polymer.

40

2 Templuted Synthesis of Polymers

When macromolecules are formed by radically initiated vinyl polymerizations, it is possible to control the formation of new stereogenic centers with suitable templates by a repetitive one-dimensional property transfer along a long chain and to obtain, e.g., structurally defined, chiral linear chains (for reviews, see [4-71). An information transfer to a plane surface in a two-dimensional manner may also occur [8, 91 or, if a crosslinking reaction is performed during the transfer, a real three-dimensional transfer can be achieved (for reviews see [ 10- 161). After the first two possibilities have been considered briefly, three-dimensional transfer in the form of the imprinting method will be discussed in some detail.

2.2 Preparation of Optically Active Linear Vinyl Polymers by Templated Synthesis As an example for a one-dimensional property transfer, the preparation of optically active co-polymers using chiral template molecules is described. In this case, the optical activity in the polymer arises from the chirality of the configurational arrangement of the main chain (main chain chirality). Symmetry considerations show that there are several possible structures both for stereoregular homo- and for co-polymers in which this type of chirality can be expected [4]. One of these structures is a stereoregular copolymer of the type shown in Figure 2-1, consisting of triads with AAB substituents along the chain.

Figure 2-1 Stereoregular, chiral copolymer with triads of the sequence AAB .

Actually, the successful synthesis of such polymers yielded the first example of an optically active vinyl polymer with main chain chirality [17]. In this case, templates used during polymerization control the composition, the stereochemistry, and the chirality of the polymer chains formed. Preparation of a structure such as that represented in Figure 2-1 was possible by the attachment of two 4-vinylphenylboronic acids to a 3,4-disubstituted D-mannitol derivative yielding the templated monomer 1. This monomer was then copolymerized with a co-monomer such as methyl methacrylate (MMA) [17,18]. As shown in Scheme 2-1, the copolymerization involves a cyclopolymerization of monomer 1, since no crosslinking

2.2 Preparution of Opticully Active Linear Vinyl Polymers by Templated Synthesis

41

occurred. The linear polymers, obtained after splitting off the template, exhibited strong optical activity. A wide variety of optically active copolymers have thus been prepared (for examples, see Table 2-1). Even optically active homopolymers are accessible by a similar route [19]. By a simple deboronation method, optically active polymers Plb, e.g., poly(styrene-co-(methyl methacrylate)), can easily be obtained. Similar asymmetric cyclocopolymerizations have recently also described by Kakuchi et al. (for a review see [201).

R'

chlrrl

I I

diad

CHz HsC--C-COOCH,

memo diad

P1 a

R=--B(OHk

b

R=H

Scheme 2-1 Schematic representation of the asymmetric cyclocopolymerization of monomer 1 with methyl methacrylate [4].

.H

I

Table 2-1 Optical activity of copolymers Pla of 1 with different co-monomers after removal of the template [18,21, 221. Co-monomer

[al%

Methacrylonitrile Methyl methacrylate Styrene 4-Vinylbenzyl alcohol 4-Chlorostyrene 4-Viny lbenzddeh yde 4-Vinylstilbene

-85" -85"

-34" -11"

+1.5"

+39" + 145"

42

2 Templated Synthesis of Polymers

Mechanistic studies revealed that this polymerization proceeds through an asymmetric cyclocopolymerization involving an unusually large 19-membered ring [ 181 (see Scheme 2-1). The optical activity stems from the formation of chiral distyryl dyads in the polymer main chain, which are induced by the chiral template molecule. The dyads are separated from one another by one or more co-monomeric units. The chirality of the polymers is, however, independent of the configuration at these co-monomeric centers. The absolute configuration of the prevailing asymmetric dyad building block has been established to be (S,S), as evidenced by the synthesis of oligomeric model compounds. Conformational analysis shows that both so-called “racemic” as well as “meso” dyads must be expected. The ratio of meso and racemic dyads could be determined by radical cyclization of 1 in the presence of an excess of azobis(isobutyronitri1e)(AIBN) to yield a monomeric cyclic compound [3,23] (Scheme 2-2). Hydrolysis of this cyclic compound and deboronation yielded four reaction products. Investigation of the reaction products showed that the two diastereomeric dyads are produced in a comparable ratio; in both cases the enantiomeric excess is very high, resulting in structures that correspond in the polymer to a mixture of (S,S) as well as (R,S)dyads. Only the (S,S) dyads (“racemic dyads”) will contribute to the chiroptical properties of the copolymers but the meso dyads (R,S) have nearly no influence. NC-C+CHJz +H2 CN

Ar-C-H

hydmlysk

A

1-

LHZ

H 4 - k NC--CICkh

NC<--(CH.3)2

~ H P H-C-FW

I

F* Ar-C-H I

HsC-CICHJZ

( 3.4 % )

(48.4 % )

( 4.0 % )

Scheme 2-2 Schematic representation of the radical cyclization of monomer 1 with AIBN and the preparation of the four stereoisomeric dimers. Only one stereoisomer is represented in the cyclization product [231.

2.3 Exact Placement of Functional Groups on the Surfaces of Rigid Polymeric Materials Using Template Molecules The two-dimensional information transfer from low-molecular-weight templates to polymers can be achieved on the surfaces, e.g., of wide-pore silica. We have attempted

2.3 Exact Placement of Functional Groups on the Surfaces

43

to introduce two amino groups onto a more or less planar surface of silica, arranged at a specific distance apart with the aid of a template (Scheme 2-3a). With this method, it was possible to locate two functional groups on a silica surface via siloxane bond formation (see Scheme 2-3b), thus enabling an investigation of the selectivity due to accuracy in distance alone [8,9].

Scheme 2-3 Introduction of two amino groups on the surface of a rigid matrix by a template molecule such as 2 or 3 after removal of the template. (a) Schematic representation of the two amino groups on a planar surface or on a surface where the remaining groups around have been capped. (b) Two amino groups on the surface of silica attached via a siloxane grouping. The remaining silanol groups have been blocked by trimethylsilyl groups [8].

44

2 Ternplated Synthesis of Polvmers

Two amino groups were attached to the surface of silica at a distance of 0.72 and 1.05 nm from one another using the template monomers 2 and 3, respectively. The attachment to the surface is achieved through the formation of siloxane bonds by condensation between the methoxysilane group of 2 and 3 and the silanol groups on the surface of the silica. Most of the remaining silanol groups were afterwards capped by reaction with hexamethyldisilazane to avoid non-specific adsorption (Scheme 2-3). Over 95% of the templates could be split off. Unlike the situation with polymers, in this case the position of the two amino groups should not be changed as a result of chain mobility, swelling, or shrinking. The distance can only be altered by conformational changes within the functional group part. For comparison purposes, a silica with randomly distributed amino groups was prepared from 4. In order to elucidate the role of accuracy in distance, the selectivity a was determined by equilibration with an equimolar mixture of the two template dialdehydes 5 and 6 (see Table 2-2). Both the silicas showed a significant difference in binding, preferring their own templates, with a values of 1.74 and 1.67. This clearly suggests that by using distance selectivity alone and with differences of only 0.33 nm (between 5 and 6), substrate selectivity can be observed. Table 2-2 Selectivity of modified silicas with each of the two amino groups at a defined distance

PI.

Splitting percen-

Distance r of groups

Apparent binding constant OHC-

0

CHO

OHC

0m

aCHO a’

v

5

Silica modified with 2 Silica modified with 3 Silica modified with 4 (at random)

2

Selectivity

6

<9S%

0.72

4.91

2.58

1.74

>9S%

1.05

9.07

13.77

I .67

-

2.26

2.05

-

Chromatography with silicas of this type could also be used to separate dicarboxylic acids that differ in the distance between their carboxyl groups. Good separations were observed compared with those obtained under identical conditions on silica with randomly distributed amino groups [ 101.

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules

45

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules 2.4.1

The Principle

A three-dimensional transfer of information from a template to a polymer consists in the preparation of crosslinked polymers by molecular imprinting with templates [24-261 (for reviews, see [ 10-16, 27, 281). For this, polymerizable vinyl monomers containing functional groups were attached to suitable template molecules by covalent or non-covalent interactions. Subsequent copolymerization in the presence of solvents and relatively large concentrations of crosslinking agents produced rigid macroporous polymers. Removal of the template molecules (Scheme 2-4) left behind chiral cavities in the polymer whose shape and arrangement of functional groups were determined by the structure of the template molecules.

m

G/ I / / / /

1

Scheme 2-4 Schematic representation of the imprinting of specific cavities in a crosslinked polymer by a template (T) with three different binding groups [lo].

This technique resembles the formation of antibodies from haptens, and actually a similar mechanism to the imprinting was formerly thought to be the mechanism of formation of antibodies [29]. The functional groups in these cavities are located at various points in the polymer chain, and are held in a definite mutual orientation simply by the crosslinking. In this case, the stereochemical information is not carried by a low-molec-

46

2 Templated Synthesis of Polymers

ular-weight part of the molecule. Instead, the entire arrangement of the polymer chains (the topochemistry) is responsible for the stereochemical structure. This is reminiscent of the structure of the active centers of enzymes; we have therefore termed these polymers “enzyme-analogous”. The relationship of the template to the imprinted cavity corresponds to the key/lock principle proposed by Emil Fischer for enzyme catalysis more than 100 years ago [30]. The imprinting process has a certain analogy to F. H. Dickey’s attempts to imprint silica gel by precipitation in the presence of template molecules [311. An example of the imprinting procedure is the polymerization of the template monomer 7, which was used for the optimization of the method [32-351. In this case, phenyl-a-D-mannopyranoside 7a acts as template. Two molecules of 4-vinylphenylboronic acid are bound by diester linkages to this template. The binding sites (the boronic acids) are bound by a covalent interaction. The monomer was copolymerized by free radical initiation in the presence of an inert solvent with a large amount of bifunctional crosslinking agent. Polymers thus obtained are macroporous and have a permanent pore structure and a high inner surface area. Polymers of this type possess good accessibility on the surface of the pores and a rather rigid structure with low mobility of the polymer chains.

7

7a

The template 7a can be split off by water or methanol to an extent of up to 95% (Scheme 2-5). The accuracy of the steric arrangement of the binding sites in the cavity can be tested by the ability of the polymer to resolve the racemate of the template, namely of phenyl-a-D,L-mannopyranoside.Therefore the polymer is equilibrated in a batch procedure with a solution of the racemate under conditions under which rebinding in equilibrium is possible. The enrichment of the antipodes on the polymer and in solution is determined by measuring the specific optical rotation and the separation factor a, i.e., the ratio of the distribution coefficients of the D and L compounds between polymer and solution, is calculated. After extensive optimization of the procedure, a values between 3.5 and 6.0 were obtained [lo]. This is an extremely high selectivity for racemic resolution that cannot be reached by most other methods.

47

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules

OH

Scheme 2-5 Schematic representation of the polymerization of 7 to obtain a specific cavity. The template 7a can be removed with water or methanol to give the free cavity [lo].

Polymers obtained by this procedure can be used for the chromatographic separation of the racemates of the template molecules [lo, 32, 351.The selectivity of the separation process is fairly high (separation factors up to a = 4.56), and, at higher temperatures with gradient elution, resolution values of R, = 4.2 with baseline separation have been obtained (Figure 2-2). These sorbents can be prepared conveniently and possess excellent thermomechanical stability. Even when used at 80 "Cunder high pressure for a long time, no leakage of the stationary phase or decrease in selectivity during chromatography was observed.

' A

-,

L 10

thin@

14

Figure 2-2 Chromatographic resolution of ~ , ~ - on 7 aa polymer imprinted with 7 (elution with a solvent gradient at 90 "C) 1351.

In the meanwhile, a large number of different templates have been used by us and many other groups in the world. An interesting extension of the concept of molecular imprinting was introduced by Mosbach and co-workers (for reviews see [ 12, 36]),who used only non-covalent interactions during imprinting and the resulting equilibration

48

2 Templated Synthesis of Polymers

studies. This approach offers new possibilities for binding because only a limited number of practical linkages are available for fast and reversible covalent binding, and because it has the advantage of easy preparation of the template assemblies. Mostly racemic amino acids were separated in this case, and high selectivity could be demonstrated (Scheme 2-6).

Scheme 2-6 Schematic representation of a cavity produced in the presence of L-phenylalanine anilide. The polymerization takes place in the presence of acrylic acid. Non-covalent electrostatic interactions and hydrogen bond formation occur [ 121.

Table 2-3 lists a wide range of examples for different chemical classes of templates that have been used for molecular imprinting in crosslinked polymers. The type of binding during the imprinting and the polymer structure will be discussed in other sections. Table 2-3 Examples of templates used for the preparation of molecularly imprinted polymers. Class of substance

Compound

Binding typea

Application

Reference

sugars

Mannose deriv. Fructose, galactose Sucrose Glucose Glucose Gluconamide Sialic acid Propanediol Mannitol Glyceric acid Mandelic acid

A A A

Enant. resolution Enant. resolution Microreactor Separation Sensor Specific membranes Sensor Enant. resolution Enant. resolution Enant. resolution Enant. resolution

132-351 [37, 381

Diols, polyols Hydroxycarboxylic acids

B C B A+B A A

A+D A

WI

[401 r411 [42] [431 1441 [25, 26,441 [24-26,45-471 [481

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules Table 2-3 (Continued). ~

~~

Class of substance

Compound

Binding typea

Application

Amino acid derivatives

Anilides Anilides Dansyl deriv. DOPA Amino acids Amino acids Amino acids N-Ac-L-Phe-L-Trp-OMe Leu-5-enkephalin

A B B D B B C B B B B B B B B B B B B B

Enant. resolution Enant. resolution Sensor Microreactor Enant. resolution Sensor Enant. resolution Enant. resolution Separation Enant. resolution Separation Separation Separation Sensor Sensor Separation Separation Separation Immunoassay Membranes

B D A D B B B B B B B

Sensors Separation Separation Microreactor Separation Separation Separation Immunoassay Separation Immunoassay Separation, enant. resolution Immunoassay Sensor Separation Separation Catalyst Separation Separation Microreactor Catalyst Microreactor Separation

Peptides

(3-L- Ala-L- Ala-OMe

Proteins Bacteria Nucleosides and nucleotides Purine derivatives

Steroids

Drugs

Dicarbonyl compounds

Disulfides Imidazole derivatives

Urease Ribonuclease A Myoglobin Listeria spp. Adenosine AMP Nucleic acid 9-Ethyladenine Theophylline Theopyhlline, caffeine Cholesterol Cholesterol Cholesterol Androstane deriv. Testosterone Pentamidine Nicotine Diazepam Cinchonine Morphine Propranolol Propranolol Chloramphenicol Dialdehydes Dialdehydes Dialdehydes Diketones Diketones Dicarboxylic acids Dicarboxylic acids Benzyl disulfides Bisimidazoles

B B A AC A A C D A A C

Reference

49

50

2 Templated Synthesis of Polyrnet-s

Table 2-3 (Continued). Class of substance

Compound

Binding type"

Application

Reference

Dyes

Methyl orange Methyl orange Rhodanile Blue Artrazine Artrazine Simazine Transition state analogues

B' B

Separation Separation Separation Separation Sensor Separation Catalyst Catalyst

[31.991 [ 1001 [loll [102-1051 [lo61

Pesticides Phosphonate esters a

B B B B B B'

[1071

[ 108- 1121

[I131

A, covalent binding during imprinting and equilibration; B, noncovalent binding during imprinting and equilibration; C, metal coordindon binding during imprinting and equilibration; D, covalent binding during imprinting, noncovalent binding during equilibration. Adenosine monophosphate. Imprinted in silica.

As Table 2-3 shows, imprinted polymers have been mainly used as separation media (mostly in chromatography). Of special interest is the enantiomeric resolution of racemates. Further applications are as immunosorbents and chemosensors. The cavities in the imprinted polymers have also been used as microreactors for selective reactions and, more interestingly, as the active sites of catalytically active polymers. In 1998 nearly 100 papers appeared in the literature on molecular imprinting, together with one book [ 1141; another book is imminent [ 1 151.

2.4.2 The Optimization of the Structure of the Polymer Network The optimization of the polymer structure was rather complicated. On one hand, the polymers should be rather rigid to preserve the structure of the cavity after splitting off the template. On the other hand, a high flexibility of the polymers should be present to facilitate a fast equilibrium between release and reuptake of the template in the cavity. These two properties are contradictory to each other and a careful optimization has to be performed in these cases. Furthermore, good accessibility of as many cavities as possible should be possible. Good thermal and mechanical stability is also necessary. Ever since the first experiments, in nearly all cases macroporous polymers have been employed which possess a high inner surface area (100-600 m2 g-') and which show, after optimization, good accessibility as well as good thermal and mechanical stability. The selectivity is mostly influenced by the lund and amount of crosslinking agent used. Figure 2-3 shows the dependence of the selectivity for racemic resolution of the racemate of 7a on polymers prepared from 7 [33, 341. Below a certain amount of crosslinking in the polymer (around 10%) no selectivity can be observed; the cavities are not sufficently stabilized. Above 10% crosslinking a steady increase in selectivity is ob-

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules

51

3.50

t

3.00 2.50 2.00 1.50 1.oo

X[%l

+

Figure 2-3 Selectivity of polymers as a function of the type and amount (X) of crosslinking agent [33]. The polymers were prepared in the presence of 7 with various proportions of the crosslinking agents: (a) ethylene dimethacrylate; (b) tetramethylene dimethacrylate; (c) divinylbenzene. After removal of the template 7a, the separation factor a = KD/KLwas determined for the resolution of ~ , ~ - in 7 a batch process.

served. Between 50 and 66% a surprisingly high increase in selectivity occurred, especially if ethylene dimethacrylate is used as a crosslinker. In this investigation, ethylene dimethacrylate appears to be superior to technical divinylbenzene or butylene dimethacrylate as a crosslinker. The inert solvent used during polymerization also has a strong influence on the polymer structure [27], but the influence on selectivity is astonishingly low. A stronger influence on the selectivity is observed if the amount of inert solvent during polymerization is raised from 0.29 to 1.76 mL g-' monomeric mixture, the optimum being around 1.O mL g-' [47]. Aside from a high selectivity, the polymers should be able to undergo a fast and reversible binding of the substrate within the cavities. For this, a certain flexibility is necessary. Cavities of accurate shape but without any flexibility present kinetic hindrance to reversible binding. Polymers obtained with ethylene dimethacrylate as crosslinker retained their specificity for a long period. Even under high pressure in a high-performance liquid chromatography (HPLC) column, the activity remained for months. This was true even when the column was used at 70-80 "C. On the other hand, polymers crosslinked with divinylbenzene gradually lost their specificity at higher temperatures. Interestingly, at 60 "C the a value for racemic resolution was further increased to 5.11. Higher selectivity at increased temperature had been observed during earlier chromatographic studies [ 116, 1 171.

52

2 Templated Synthesis of Polymers

In most cases, the macroporous imprinted polymers are prepared in bulk and are then crushed and sieved. Thus, by a rather tedious procedure, irregularly broken polymers are obtained. Usual suspension polymerization is not possible with most non-covalent and even with some covalent bindings since water interferes with the binding reaction, and hampers an efficient imprinting. By using new types of stoichiometric non-covalent binding, these difficulties can be overcome and polymers can be prepared by standard suspension polymerization methods [I 181. Uniformly sized particles are thus easily obtained. Another possibility is a suspension polymerization in media other than water. For example, a suspension polymerization using a liquid perfluorinated alkane as the dispersing phase was reported [ 1191. In other cases, a two-step swelling and polymerization method was applied to prepare molecularly imprinted beads [ 1201. A further possibility is to use silica-based supports, which are available in a broad range of bead sizes and pore diameters. These beads can easily be modified by silanizing reagents carrying polymerizable groups. On this surface, a thin layer of a monomeric mixture containing the template is polymerized. Thus the beads can be coated with imprinted polymers for the separation of dyes [ 1211, enantiomeric sugars [ 122, 1231, or bisimidazoles [ 1241. These coated silicas show very good properties as chromatographic supports; their drawback is the lower loading capacity compared to macroporous polymers. It is also possible to use trimethylol trimethacrylate-based beads and to cover these as described before [ 1251. Imprinting in thin layers on the surface of other materials offers the possibility of a surface imprinting procedure. High-molecular-weight templates cannot be imprinted in the usual manner in a bulk polymerization since, after crosslinking, the templates cannot be removed. Therefore enzymes have been used as templates by a surface imprinting method [64, 651. Especially interesting is the possibility of imprinting even such large objects as bacteria. First reports of work in this direction have appeared [67, 68, 1261, and it remains to be seen how selectively these imprints distinguish between different species of bacteria. It appears advantageous to use for molecular imprinting an in-situ method that has been developed previously for reversed-phase HPLC [127]. In this case, the polymer is directly prepared inside the column. It has been shown that this method is applicable for molecular imprinting [54, 79, 127, 1281 but the selectivity for separation in these columns is somewhat reduced.

2.4.3 The Role of the Binding-site Interactions In the imprinting procedure, the binding groups have several functions [ 10, 14, 129, 1301. On one hand, the bond between the template and the binding group should be as strong as possible during the polymerization. This enables the binding groups to be fixed by the template in a definite orientation to the polymer chains during the crosslinking polymerization. It should then be possible to split off the templates as completely as possible. A very important function is the interaction of the binding groups with the sub-

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules

53

strates to be bonded: for example, with the compound that acted as the template. This interaction should take place as rapidly and reversibly as possible, so that the chromatographic process or catalysis will be rapid. Thus, although a high activation energy is desirable for the first function, it should be as low as possible for the other two. Detailed investigations have shown that the selectivity in enantiomeric resolution is dependent both on the orientation of the functional groups inside the cavities and the shape of the cavities [37,38, 131, 1321. The dominating factor, though, is the orientation of the functional group inside the cavity [37]. If two binding sites per template have been used, several mono-point bindings can occur but only one two-point binding [lo, 1231. It is the two-point binding that provides high selectivity. Therefore, this portion has to be increased, which is possible, e.g., by increasing the temperature [ 1331. Another problem of binding is the reuptake of template in the cavity. In the case of covalent binding and all other types of stoichiometric binding, binding sites are situated only in the cavity. After removal of the template, this usually leads to a swelling in the cavities which guarantees a high proportion (90-95%) of reuptake after the first removal [ 101.At the same time, it facilitates a quick mass transfer during equilibration of the template with the polymer (Scheme 2-7). On reuptake of the template, the cavity shnnks to its original volume. This behaviour is similar to the inducedjit known from enzyme chemistry.

Scheme 2-7 Schematic representation of the removal from a polymer of the template 7a bound by covalent binding and the swelling of the cavity. Afterwards, 90-95% of the cavities can be reoccupied [ 101.

On the other hand, during non-covalent imprinting, e.g., with acrylic acid, a fourfold excess of binding sites has to be used in order to obtain good selectivity. Under these conditions the binding sites are distributed all over the polymer (Scheme 2-8). As was found recently (501 under these conditions, only 15% of the cavities can take up a template again, the remaining 85% being lost irreversibly for separation. This might be due

2 Templated Synthesis of Polymers

54

to a shrinking of the majority of the cavities. Therefore these imprinted polymers are not well suited for preparative separations and for investigations on catalysis. In consequence, new and better binding sites should be devised.

Scheme 2-8 Schematic representation of the removal of the L-phenylalanine-anilide template bound by non-covalent interaction. Owing to the large excess of carboxyl groups, a substantial part of the cavities may shrink. Only around 15% of the cavities can be reoccupied [ 101.

The boronic acid behaves quite satisfactorily as a binding site since it gives a strong interaction during the imprinting, and the binding during equilibration can be accelerated by addition of suitable bases such as ammonia or piperidine. In this case, the trigonal boron is transformed to the more reactive tetragonal form (Equations (a) and (b)). Unfortunately, there are not many examples of good binding through covalent bonds. For noncovalent binding, methacrylic acid has been replaced by more acidic compounds such as sulfonic acids [ 1341 or fluorinated carboxylic acids [ 1351, but there is no major improvement.

- NH3

1

+N Y

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules

55

An interesting type of binding during polymerization and later in the final polymer can be achieved by coordinative bonds to metals. This type of bond is analogous to that used in ligand exchange chromatography. The advantage of this kind of bond is that its strength can be controlled by experimental conditions. Definite interactions occur during the polymerization, and an excess of binding groups is not necessary. The subsequent binding of the substrate to the polymer is so rapid that in many cases even rapid chromatography is possible. This method was first used for imprinting by Fujii et al. [58]. They obtained a remarkably high selectivity in the optical resolution of N-benzyl-D,L-valine using a chiral Schiff base ligand of (1R,2R)-I ,2-diaminocyclohexane and 4-(4-vinylbenzy1oxy)salicylaldehyde to which amino acids could be bound through a Co3+ cation. The exceptionally high separation factor a for the racemate resolution of the template molecule was found to be 682. The enantiomeric excess (e.e.) was 95.5% in the batch process. More detailed investigations showed that most of the separating ability was due to the cavity effect. The observed selectivity is greater than that of many enzymes. Unfortunately, the mass transfer rate in the case of the Co3+complex is very slow in the chromatographic separation, so that practical separations are very difficult. Recently, Arnold, Dhal et al. investigated the bonding of imidazole-containing compounds with Cu2+complexes such as 8 in great detail (Equation (c)) [13,97,98]. Model experiments were first carried out in which bisimidazoles with various distances between the imidazole groups were used as templates to position polymerizable iminodiacetate groups in the polymer. These experiments were aimed at developing an effective recognition for proteins that depends on the correct spatial arrangement of a few binding sites on a polymer [ 131.

6

d+-$ ,---- d++?

N I __-cb

a

0

0

-L

LG II I Q 0

y4-4;;-0 II

~

Another even more promising approach uses tetraazacyclononane-Cu*+ chelates 9 for binding. With this binding site it is possible to bind, e.g., glucose [41] as well as free amino acids [59].

56

2 Ternplated Synthesis of Polymers

The amidine binding site possesses very promising properties for the binding of carboxylic acids or phosphonic monoesters. Since these complexes tend to be insoluble, a number of derivatives have been prepared [136, 1371. Especially suitable is the 4-vinyl-N,N'diethylphenylamidine 10 [ 1121 (see Equation (d)). Association constants in these equilibria of 104-l O6 dm3 mol-', depending on the solvent, are observed. Splitting off the templates is easily possible and also the equilibrations are very quick. A reverse interaction of an amidine-containing drug (pentamidine) and acrylic acid has been used previously [79].

Binding constants in hydrogen bonding increase with multiple interactions during ring formation. Thus an investigation on the binding of amidopyrazoles with dipeptides was performed in our institute [138, 1391. It is expected that under these conditions one amidopyrazole is bound to the top face of the dipeptide via three-point binding whereas the second goes to the bottom face via two-point binding. Complexation should stabilize the Psheet conformation in the dipeptide (Figure 2-4). NMR titrations of Ac-L-Val-L-ValOMe with 3-methac~yloylaminopyrazole show large but markedly different downfield shifts for both peptide amide protons, one oriented to the upper and the other to the lower site. When one equivalent of 5-amidopyrazole is added, only complexation from the top by three-point binding with an association constant of 80.0 dm3 mol-' is observed. On further addition of 5-amidopyrazole, complexation from below by two-point binding occurs with an association constant of only 2.0 dm3 mol-'. In both complexes the dipeptide possesses a Psheet conformation. By variation of the acid part of the amide the association constant can be further substantially increased ( K = 890 dm3 mol-' for CF,-CO-). Thus the binding site monomer 11 has been used successfully for imprinting with dipeptides and for racemic resolution of the racemate of the dipeptide template [139]. Multiple interactions are also used with the new binding site 2,6-bis(acrylamido)pyridine. In this case, different barbiturate drugs, such as cyclobarbital, act as templates [ 1401. Retentions vary, depending on the barbiturate.

2.4 Molecular Imprinting in Polymeric Materials Using Templute Molecules

57

0

Figure 2-4 Side and top views of the computer-calculated 2 : 1 dipeptide-amidopyrazole complex [ 1383. When seen from above, the heterocycle on the top side is symbolized by a horizontal bar (for clarity, the second heterocycle is omitted).

11

2.4.4 Chiroptical Properties of the Crosslinked Polymers Usually the chiroptical properties of highly crosslinked polymers cannot be measured. The asymmetry of the empty cavities can be analyzed by the excellent racemate resolution ability. By a new method it can now also be directly detected by measuring the optical activity [133]. This is measured by suspending the polymer in a solvent which has the same refractive index as the polymer, a technique which was developed for other types of insoluble polymers [ 1411. The molar optical rotation values thus measured are shown in Table 2-4. Table 2-4 Molar optical rotation values for polymers with chiral cavities [133].

[MI% a

Template monomer 7

Polymer P E' with template 7a

Polymer P E template 7a split off a

-448.9'

-61.7'

+110.0"

As the ethylene glycol ester.

58

2 Templated Synthesis of Polymers

If we compare the value -61.7" for a polymer prepared from 7 (calculated for the molar content of 7), still containing the template, with the value -448.9" for the template monomer 7, it becomes apparent that the molar optical rotation has decreased considerably as a result of polymerization. This could have several causes, one being the influence of the polymer matrix. Its effect can be determined by splitting off the optically active template 7a. If the boronic acids are converted with an achiral diol to the corresponding ethylene glycol ester, the polymer gives a positive molar rotation ([MI& = + I 10.0'). This shows that in P E (Table 4), the imprints generated in the polymer make a positive contribution to the optical rotation value. Measuring the optical rotation in the solid phase thus allows the properties of chiral cavities in the polymer, such as the binding situation of a bound substrate, different swelling situations, etc., to be determined directly. If, for example, a polymer with empty cavities is recharged with the template, the resulting polymer, in contrast to P E' (with template), has a very large positive rotation value ([MI& = +323"). If this loaded polymer is heated in acetonitrile in the presence of a 3 A molecular sieve, the molar rotation [W$, changes to -68", i.e,. to about the same value as for the original polymer with template. Evidently most of the template molecules are first bound only by a single point of attachment (formed by esterification of only one boronic acid group in the cavity), and this then changes to a double attachment. At higher temperature most of the template is quickly bound by a two-point binding. The optical rotation of these polymers without templates is not caused by individual chiral centers, as is usual, but by the boundaries of the empty imprints as a whole. Their chiral construction and conformation are stabilized by means of the crosslinking of the polymer chains. It is unlikely that the chiral configurations of the linear portions of the chains contribute to the asymmetry of the cavity since no asymmetric cyclocopolymerization is possible for the template monomer 7. With other types of template monomers, though, such contributions of backbone chiral portions of the polymer might be expected (see Section 2.2).

2.4.5 Chromatography Using Molecularly Imprinted Polymers Molecularly imprinted polymer networks have been used as stationary phases in chromatography, especially for the resolution of racemates. Although the selectivity was good, strong peak broadening in the chromatographic process at first made it impossible to obtain complete separation, for example, of the racemate of template 7a. When significantly more selective adsorbents and improved chromatographic processes coupled with higher temperatures became available, in 1986 we were able, for the first time, to perform a complete racemate resolution with R, = 2.1 [117]. Later, we achieved resolutions of R, = 4.3 by using gradient elution [35] (see Figure 2-2). With non-covalent interactions, for example using the polymer described in Scheme 2-6, it was thought that a separation would have been much easier to achieve. However, these systems were found to be very complicated in chromatographic practice. Strong

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules

59

interactions with the medium occurred, and the mass transfer was also very slow. In 1988 Mosbach et al. [36] obtained a complete resolution with R, = 1.2, and Sellergren and Shea [ 1421 achieved considerable improvement five years later after very careful optimization work. Protonation of the substrate could be obtained in an aqueous buffer system, pH = 4.0, in which the carboxyl groups inside the cavities were partially deprotonated and those outside the cavities were not deprotonated at all. This gave selective binding by an ion-exchange mechanism only inside the cavities. Kinetics were good, and could be further improved by use of a heat-treated polymer to give a resolution of R, = 2.2. Remarkably, in these separations the more strongly retarded enantiomer (corresponding to the template molecule) gives much more pronounced peak broadening if a solvent gradient is not used during chromatography. The number of theoretical plates for this compound is at most half that of the less strongly retarded compound. The reason must be essentially the two-point binding of the template molecule and the one-point binding of the other enantiomer. The difference also shows itself in the temperature dependence of the number of theoretical plates for the two enantiomers. Whereas the template molecule shows hardly any temperature dependence because of the increased two-point binding with slow binding rates at higher temperatures, the number of theoretical plates for the second enantiomer increases rapidly, as expected (Figure 2-5a) [117]. The effect of concentration on retention is also very different for the two enantiomers (Figure 2-5b). The “wrong” enantiomer does not show much effect, whereas the retention in the case of the template molecule is greatly increased at lower concentrations at which only the most selective cavities are occupied by the template molecule. The selectivity therefore increases sharply [so].

a

b

1000

500 400 D- PAA

T[OC] +

UMOlPAA

-

Figure 2-5 Differences in the effect of temperature on the number of theoretical plates, and in the effect of the amount chromatographed on the retention for template molecules and their enantiomers. (a) Temperature dependence of the number of theoretical plates (Nth)in the resolution of D-7a and L-7a on a polymer imprinted with 7 [I 171. (b) Dependence of the capacity factor k’ on amount treated in the resolution of L- and of D-phenylalanine-anilide on a polymer imprinted with

L-phenylalanine-anilide [50].

60

2 Terndated Synthesis of Polvrners

Preparative separations are also possible. For example, 30 mg of the racemate of 7b were effectively resolved by 20 g of polymer[l43].

2.4.6 Catalysis With Molecularly Imprinted Polymers One reason for producing cavities with a definite shape and a predetermined arrangement of functional groups is the desire to perform stereoselective and regioselective reactions in these cavities, which are then termed “microreactors”. This is an interesting example of the “template” terminology. A so-called template is used to prepare an imprint of a specific shape containing functional groups in a certain stereochemistry. This imprint is then used as a real template to control reactions performed inside the templated cavity. This might be one of the rare examples of using real templates. The cavity is first imprinted with the end product of the reaction, and a precursor is then embedded into the cavity so that a reaction can convert it into the product. The first experiments were carried out by the research groups of Shea [92] and Neckers [93], who performed cycloadditions to obtain cyclopropanedicarboxylic and cyclobutanedicarboxylic acids. The latter compounds were obtained with remarkable regio- and diastereoselectivity. The first asymmetric syntheses in the chiral cavity were achieved in our research group [27, 52, 531. A cavity was made with an L-DOPAmethyl ester. After removal of the template, glycine was embedded in the cavity, deprotonated, and alkylated. So far, the highest enantiomeric excesses (36% e.e.) on using imprinted polymers have been with the amino acids formed in this way. This excess is purely a result of the shape of the asymmetric cavity. In some very remarkable experiments, Bystrom et al. [77] were recently able to demonstrate high regio- and stereoselectivity in reactions inside the imprinted cavity. The steroid 12 was copolymerized as the template monomer, and removed by reduction. The hydroxyl group in the polymer newly formed from the carboxyl group was converted into an active hydride by LiAlH,. With the help of this polymer, androstan-3,17-dione was reduced to the alcohol exclusively in position 17, whereas in solution or with a polymer with statistically distributed hydride groups it is reduced exclusively in position 3.

12

Imprinting should also be an excellent method to prepare active sites of enzyme analogues. I t has already been reported that antibodies prepared against the transition state

2.4 Moleculur imprinting in Polymeric Materials Using Template Molecules

61

of a reaction show considerable catalytic activity (for review, see [ 1441). Thus, antibodies prepared against a phosphonic ester (as a transition state analogue for the alkaline ester hydrolysis) enhanced the rate of ester hydrolysis by 10’-lo4 fold. In this case, it was also possible to obtain an asymmetric catalysis since the antibodies provide an asymmetric active site. The same should be possible with imprinted polymers (for reviews see [ 145, 1461). Initial attempts of different groups [ 108- 1111 to use this concept for the preparation of catalytically active imprinted polymers for ester hydrolysis had been rather disappointing. Enhancements of 1.6-and 2-fold, in one case of 6.7-fold, are quite low and should be improved. Better results were obtained for the catalysis of the dehydrofluorination of 4-fluoro-4(4-nitropheny1)butanoneby Shea et al. [94] and Mosbach et al [ 1471. Shea used benzylmalonic acid as the template to position two polymerizable amines in a definite arrangement in the cavity. After removal of the template, dehydrofluorination was enhanced by this catalyst by a factor of 8.6. Even stronger accelerations (25-fold) were obtained during decarboxylations of 3carboxybenzisoxazoles [88]. In this case two amino groups were placed a suitable distance apart in the cavity by means of a polymerizable di-Schiff base. Morihara’s research group worked very intensively on preparing catalysts on the surface of silica gel (see, e.g., C113, 1481). In a process described as “footprint catalysis”, commercial silica gel is treated with Al” ions and imprinted with a transition-state analogue. Similar accelerations to those of the foregoing examples were obtained. It appears that the shape of the transition state alone does not lead to sufficient catalysis; in addition, catalytically active groups have to be introduced. This is also true for catalytic antibodies, since Benkovic et al. [ 1491 showed that, e.g., a guanidinium group (of the amino acid L-arginine) plays an important role in the catalysis of the basic hydrolysis of esters by a catalytic antibody. We have therefore applied amidine groups both for binding and catalysis, investigating the alkaline hydrolysis of ester 13 [112]. Phosphonic monoester 14 was used as a transition state analogue for templating. Addition of two equivalents of the new binding site monomer 10 furnished the bisamidiniurn salt. By the usual polymerization, workup, and removal of the template, active sites were obtained with two amidine groups each. Owing to the stoichiometric interaction of the binding sites, the amidine groups are only located in the active sites (Scheme 2-9). At pH 7.6, the imprinted polymer accelerated the rate of hydrolysis of ester 13 by more than 100-fold compared to the reaction in solution at the same pH (Equation (e)). Addition of an equivalent amount of monomeric amidine to the solution only slightly increased the rate. Polymerizing the amidinium benzoate gave a somewhat stronger enhancement in rate.

62

2 Templuted Synthesis of Polymers Scheme 2-9 Schematic representation of the polymerization of monomer 14 in the presence of two equivalents of 10a (A), splitting off 14 (B), and catalysis causing alkaline hydrolysis of 13 through a tetrahedral transition state (C) [112].

B

2.4 Molecular Imprinting in Polymeric Materials Using Template Molecules

63

Table 2-5 Relative rates of hydrolysis of 13 with different catalysts in buffer solution at pH = 7.6 (Equation (e)) [112]. ~

~

Blank

With 10b

With a polymer imprinted with 10a benzoate

With a polymer imprinted with 14 and 10a

I .o

2.4

20.5

102.2

These examples showed the strongest catalytic effects obtained until that time by the imprinting method. Even when compared to antibodies, only one to two orders of magnitude are lacking. This is especially remarkable since we used “polyclonal” active sites and rigid, insoluble polymers. It should also be mentioned that these hydrolyses occur with non-activated phenol esters and not, as in nearly all other cases, with activated 4nitrophenyl esters. In order to see whether or not these polymers show typical enzyme analogue properties, we investigated the kinetics of the catalyzed reaction in the presence of various excesses of substrate with respect to the catalyst. Figure 2-6 shows the typical Michaelis-Menten kinetics observed. Saturation phenomena occur at higher concentrations. 1.4 1.2

1.0 0.8 0.6 0.4

--------

0 0.000

0.004

0.008

0.012

0.016

0.020 CFI]

Michaelis - Menten diagram for the hydrolysis of the model ester in presence of: -C-

transition state 14 imprinted polymer

--cpolymer imprinted with amidinium-benzoate --C hydrolysis in solution of pH = 7.6 in presence of amidine 10b - 0 . hydrolysis in solution of pH = 7.6

-

Figure 2-6 Michaelis-Menten kinetics of the hydrolysis of 13 according to Equation (e) in the presence of different catalysts. The initial rates are plotted versus substrate concentration [ 1121.

64

2 Templated Synthesis of Polymers

This shows that all active sites are then occupied and that the reaction becomes independent of substrate concentration. In contrast, in solution, and in solution with the addition of amidine, a much slower linear relationship is observed, The amidinium benzoate shows also some type of Michaelis-Menten kinetics. The benzoate therefore acts as a less effective template. The Michaelis constant K,,, was determined to be 0.60 mM. Turnover is relatively low (k,,, = 0.4 x m i d ) but is definitely present. Furthermore, we found that the template molecule itself is a powerful competitive inhibitor with Ki = 0.025 mM, i.e., it is bound more strongly than the substrate by a factor of 20. It is remarkable that such a strong binding of substrate and template occurs in water-acetonitrile ( 1 : I). Binding in aqueous solution by usual electrostatic or hydrogen bonding is much weaker. We observed some product inhibition similar to that by catalytic antibodies. In the case mentioned, the rate of reaction was calculated from the amount of released acid. If the calculation is based on phenol release, the rate of enhancement is nearly doubled. Hydrolysis of carbonates should avoid this difficulty. Therefore, diphenyl phosphate was used as a template, and the hydrolysis of diphenyl carbonate was then investigated [ 1501. Compared to solution, an enhancement of 982-fold was obtained and typical Michaelis-Menten kinetics was observed (vmax = 0.023 mM min-', K,,, = 5.01 mM, k,,, = 0.0115 min-I, k , , , / ~ , , ,= 2.306 min-l M-'). In very recent experiments [ 15 11 we could show that by optimizing the polymer structure the enhancement of reaction rate of the imprinted polymer compared to the polymer with statistically distributed amidine groups could be further improved. In another approach, an imprinting using labile covalent interactions was used very recently [152]. A template monomer was used to introduce a transition state analogous structure and at the same time a dicarboxylate moiety. In this case an enhancement of 120-fold compared to the solution and 55-fold compared to a control polymer containing statistically distributed dicarboxylates was obtained.

2.4.7

Outlook

The preparation of polymers and other materials with molecularly imprinted cavities has now reached a high degree of sophistication. The application of these materials is becoming more and more interesting. First industrial applications of imprinted materials are envisaged, especially as stationary phases in chromatography, e.g., for the resolution of racemates. Other interesting applications can be seen in membranes and in sensors. At present, several research groups are engaged in preparing suitable layers or membranes for this purpose. Compared to biosensors, these layers are far more stable and they can be prepared for a large variety of compounds. Compared to standard chemosensors they are far more selective, so that there is a good chance of a broad application. It is still necessary to develop extremely sensitive methods for detecting substances bound to the imprinted membrane. At present, conductometry [57, 70, 71, 106, 153, 1541, capacitance [ 1551, pH-potentiometry [41], voltammetry [69], optical detection [87, 1561,

2.5 ExDerimental Procedures

65

fluorescence [43, 51, 67, 681, and polarized UV [ 1571 have been used for detection (for review see [158, 1591). The use of imprinted polymers for radioimmunoassays has also been described [74, 82, 1601. In this case, imprinted polymers were used instead of antibodies. It is clear that these compounds cannot compete with monoclonal antibodies with regard to selectivity, but they are much easier to prepare and might therefore find application in several cases. Reactions inside imprinted cavities are another interesting area. Of great importance to the field is catalysis with imprinted polymers and imprinted silicas. For a broader application of molecularly imprinted polymers further improvement of the method will be necessary. The following problems are in the forefront of investigation today: Direct preparation of microparticles by suspension or emulsion polymerization. This problem has already been discussed. Imprinting procedures in aqueous solutions. As mentioned previously, water interferes with binding since hydrogen bonding is drastically reduced in water and, e.g., boronic esters are hydrolyzed. However, it will still be necessary for many templates to work in water. Furthermore, if the imprinting is performed in an organic solvent and the equilibrations are done in water, the binding mechanism and the selectivity might be completely different. Imprinting with high-molecular-weight biopolymers or even with bacteria. This is difficult: high-molecular-weight compounds cannot be extracted from a highly crosslinked bulk polymer, and therefore a type of surface imprinting has to be applied. Development of new and better binding sites in imprinting, as has been indicated in Section 2.4.3. Improvement of the mass transfer in imprinted polymers. This is necessary for rapid chromatographic separations, especially on a preparative scale. Reduction of “polyclonality” of the cavities, which is still a severe problem. Increase in capacity of chromatographic columns, especially with non-stoichiometric non-covalent interactions, as pointed out before. Development of extremely sensitive detection methods for use in chemosensors. Development of suitable groupings for catalysis.

2.5 Experimental Procedures 2.5.1 Polymer from Scheme 2-5 2.5.1.1 Preparation of template monomer 7 [MI Phenyl-am-mannopyranoside (7a) (6 g; 23.4 mmol) and tris(4-vinylpheny1)boroxin (6.075 g; 15.6 mmol) were heated in benzene with removal of the water by azeotropic distillation. After complete removal of water, the solvent was evaporated, and the residue was crystallized from diethyl ether. Yield: 9.7 g (86%),m.p. 139 “C.

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2.5.1.2 Preparation of the polymer [35] Template monomer 7 (0.75 g), AIBN initiator ( 1 20 mg), crosslinker ethylene dimethacrylate (15.0 g) in tetrahydrofuran (15.0 g) were filled into a tube, carefully degassed by three freeze-thaw cycles, sealed under argon, and polymerized for four days at 65 "C. The tube was then cooled and broken, and the polymer was milled with an Alpine Contraplex 63 C, and sieved to a grain size of 125- 163 pm. Alternatively, the polymer could be milled to a finer powder and separated to a particle diameter fraction of 8- I5 pm by a wind-sieving machine (Alpine Multiplex 100 MRZ). This material was first extracted with dry diethyl ether before being dried in vacuum at 40 "C. The template was removed from the polymer by a continuous extraction with methanol-water (250 mL per g of polymer). After the solvent was evaporated, the residue was dissolved in a defined volume of methanol and the content of 7a was determined polarimetrically. This polymer possessed an inner surface area of 322 m2 g-', a splitting percentage of the template of 82%, a swelling ability in methanol of 1.20, and an a value of 4.52.

2.5.2 Polymer from Scheme 2-6 2.5.2.1 Thermally initiated polymerization [36] Ethylene dimethacrylate (5.64 g), methacrylic acid (0.52 g; 6.0 mmol), L-phenylalanine anilide (0.25 g; 1.5 mmol), and of AIBN (60 mg) in acetonitrile 98.2 mL) were mixed in a glass tube. After degassing, the tube was sealed under nitrogen and consecutively heated for 24 h each at 60,90, and 120"C. Subsequently, the polymer was ground and subjected to continuous extraction in acetonitrile for 24 h. To determine the recovery of imprint molecules, the extracted anilide was quantitatively determined and the polymer was investigated by nitrogen elemental analysis before and after extraction of the imprint molecule. According to these methods about 90% of the imprint molecules had been removed from the polymers. For chromatographic purposes the polymers were first milled, then sieved in a windsieving machine (Alpine Multiplex 100 MZR). Separation factor a for the separation of D,L-phenylalanine anilide was 3.5. The chromatographic separation showed a resolution R, for the racemate of 1.2.

2.5.2.2 Photochemically initiated polymerization [50] To ethylene dimethacrylate (3.8 mL; 20 mmol), methacrylic acid (0.34 mL; 4 mmol), and L-phenylalanine anilide (240 mg; 1 mmol) in CH2Cl2(porogen) (5.6 mL) were added AIBN (40mg; 0.25 mmol) as initiator. The mixture was transferred to a 50 mL thickwalled glass tube, degassed during three freeze-thaw cycles, and sealed under vacuum. The polymerization was performed at 15 "Cin a thermostated water bath. The tube was placed at approx. 10 cm distance from the UV light source (medium-pressure mercury vapor lamp (Conrad-Hanovia) of 550 W with 33 W in the 320-400 nm interval) and turned at regular intervals for a symmetric exposure. After 24 h, the tubes were crushed,

2.5 Experimental Procedures

67

and the polymer was then ground in a mortar, followed by Soxhlet extraction with methanol for 12 h. Template recovery was determined by HPLC on a reversed-phase C,, column using p-aminophenyl acetate as internal standard and MeOH/3% HOAc (1 : 1) as eluent. By this method 60-70% of template was directly recovered. The polymers were then dried overnight under vacuum at 50°C and sieved to a 150-250pm and a 25-38 ym particle size fraction. The polymer thus obtained was gel-like, with an inner surface area of 3.8 m2 g-'. Swelling in acetonitrile was 2.01. For chromatographic separations the performance was improved by dry heating of the sorbent for 17 h at 120 "C. The a value for the separation of D,L-phenylalanine anilide was 2.3; chromatographic separation showed a resolution for the racemate of R, = 1.9.

2.5.3 Polymer from Scheme 2-9 [136,137] 2.5.3.1 N-Ethyl-4-vinylbenzamide 4-Vinylbenzoic acid chloride [161, 1621 (81.60 g; 0.49 mol) in dry CH2C12 (100 mL) was dropped into a solution of ethylamine (45.09 g; 1.00 mol) in dry CH2C12(250 mL) at -20 "C. After it had been warmed to ambient temperature, phenothiazine (0.20 g) was added. The solution was stirred for 15 h. The precipitated ethylammonium chloride was filtered off and washed with a small amount of dry CH2C12.The solvent was removed in vacuo and the residue recrystallized from EtOAc to give colorless crystals (172.4 g, 98%).

2.5.3.2 N-Ethyl-4-vinylbenzocarboximideacid ethyl ester

N-Ethyl-4-vinylbenzamide(39.95 g; 0.228 mol) was added to a solution of triethyloxonium tetrafluoroborate (58.5 g; 0.308 mol) in dry CH,C12 (150 mL) under argon.The solution was stirred for 2 h at ambient temperature, phenothiazine (0.20 g) was added, the stirring was continued for 36 h, and the solvent removed in vacuo. Remaining oil was treated with 3 M NaOH (80 mL)and directly extracted with ice-cooled Et20 (250 mL). The aqueous layer was extracted another four times with Et20, the combined organic layers were dried over Na2S0,, filtered, concentrated in vacuo, and distilled to give a colorless liquid (46.19 g, approx. loo%, b.p. 53 "C, mbar).

2.5.3.3 N,N'-Diethyl-4-vinylbenzamidine (10a) Dry ethylammonium chloride (63.61 g; 0.78 mol) was added to a solution of N-ethyl-4vinylbenzocarboximide acid ethyl ester (121.97 g; 0.60 mol) in dry EtOH (270 mL) under argon. After the mixture had been stirred at 15"C for 5 h, 4-tert-butylbrenzcatechol (0.5 g) was added, the stirring was continued for five days at ambient temperature, and the solvent was removed in vacuo. The residue was treated with ice-cooled 6 M NaOH (500 mL) and directly extracted with an ice-cooled mixture of EtOAc/Et20 ( 1 : 1). The

68

2 Templated Synthesis of Polymers

aqueous layer was extracted another four times, and the combined organic layers were dried with Na2S0,. The solvent was removed in vacuo, and the residue was sublimed twice at 0.01 mbar to give white crystals (105.24 g, 87%, m.p. 76 "C).

2.5.4 Preparation of the polymer [112] The polymer was prepared similarly to the first example from a mixture of ethylene dimethacrylate (4.67 g), methyl methacrylate (0.22 g), N,N'-diethyl-4-vinylbenzamidine (10a) (0.442 g; 2.188 mmol) template 14 (0.350 g; 1.094 mmol), AIBN (56.8 mg), and tetrahydrofuran (5.64 mL) as the porogen. Polymerization in a sealed ampoule was carried out for 70 h at 60 "C.After the usual workup procedure, the template was removed from the particles by extraction with methanol, followed by washing twice with 0.1 M NaOWacetonitrile (1 :l), water, and acetonitrile. The recovery of the template from the washings was determined by HPLC [RP8-column, eluent 0.2% trifluoroacetic acid in water/acetonitrile (55:45)]. Recovery of template was 85%. The inner surface area of the polymer amounted to 228 m2 g-' ,and the swelling ratio in methanol was 1.45. This polymer was used for the experiments described in Table 2-5 and Figure 2-6.

Acknowledgment These investigations were supported by financial grants from the Deutsche Forschungsgemeinschaft, Minister fur Wissenschaft und Forschung des Landes Nordrhein-Westfalen, and Fonds der Chemischen Industrie.

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[120] K. Hosoya, K. Yoshizako, N. Tanaka, K. Kimata, T. Araki, J. Haginaka, Chem. Lett. 1994, 1437- 1438. [I211 0. Norrlow, M. Glad, K. Mosbach, J. Chromatogr: 1984,299, 29-41. [ 1221 G. Wulff, D. Oberkobusch, M. Minhik, React. Polym. Ion Exch. Sorbents 1985,3,261-275. [ 1231 G. Wulff, D. Oberkobusch, M. Minirik, in Proceedings ofthe XVlllth Solvay Conference on Chemistry, Brussels 1983 (Ed.: G. v. Binst), Springer Verlag, Berlin, 1986, pp. 229-233. [124] S. D. Plunkett, F. H. Arnold, J. Chromatogx Sect. A 1995, 708, 19-29. [125] F. H. Arnold, S. Plunkett, P. K. Dhal, S. Vidyasankar, Polym. Prepl: (Am. Chem. Soc. Div. Polym. Chem.) 1995,36, 97-98. [I261 E. Vulfson, C. Alexander, M. Whitcombe, Chern. Bx 1997,23-26. [127] J. Matsui, Y. Miyoshi, R. Matsui, T. Takeuchi, Anal. Sci. 1995, 11, 1017-1019. [128] B. Sellergren, J. Chromtogx Sect. A 1994,673, 133-141. [I291 G. WUlff, TZBTECH 1993, 11, 85-87. [130] G. Wulff, Mol. Cryst. Liq. Cryst. 1996,276, 1-6. 11311 D. J. O’Shannessy, L. I. Anderson, K. Mosbach, J. Mol. Recognit. 1989,2, 1-5. [132] K. J. Shea, D. Y. Sasaki, J. Am. Chem. SOC.1989,111, 3442-3444. [I331 G. Wulff, G. Kirstein, Angew. Chem. 1990, 102, 706-708; Angew. Chem., Int. Ed. Engl. 1990,29,684-686. [134] I. R. Dunkin, J. Lenfeld, D. C. Shemngton, Polymer 1993,34, 77-84. [135] J. Matsui, Y. Miyoshi, T. Takeuchi, Chem. Lett. 1995, 1007- 1008. [136] G. Wulff, R. Schonfeld, M. Griin, R. Baumstark, G. Wildburg, L. HauBling (BASF AG), German Patent, Offenlegungsschrift DE A 197 20 345 A 1,1998. [137] G. Wulff, R. Schonfeld, unpublished work; R. Schonfeld, PhD Thesis, University of Diisseldorf, 1998. [I381 T. Schrader, C. Kirsten, J. Chem. Soc., Chem. Commun.1996,2089-2090. [139] C. Kirsten, T. Schrader, J. Am. Chem. SOC. 1997, 119, 12061-12068; C. Kirsten, Doctoral Dissertation, University of Diisseldorf, 1997. [140] K. Tanabe, T. Takeuchi, J. Matsui, K. Yano, K. Ikebukuro, I. Karube, J. Chem. SOC.,Chem. Commun. 1995,2303-2304. [141] P. Pino, I. Bartus, 0. Vogl, Polym. Prepr: (Am. Chem. SOC. Div.Polym. Chem.) 1988, 29, 254-255. [142] B. Sellergren, K. J. Shea, J. Chromatogl: Sect. A 1993,654, 17-28. [143] G. Wulff, M. Minhik, in Chromatographic C h i d Separations (Eds.: M. Zief, L. J. Crane), Marcel Dekker, New York, 1988, pp. 15-52. [144] R. A. Lerner, S. J. Benkovic, P. G. Schultz, Science 1991,252, 659-667. [ 1451 F. Locatelli, P. Gamez, M. Lemaire, Stud. Surjiace Sci. Catal. 1997, 108, 517-522. [146] M. E. Davis, A. Katz, W. R. Ahmad, Chem. Muter: 1996,8, 1820-1839. [147] R. Miiller, L. I. Anderson, K. Mosbach, Makromol. Chem., Rapid Commun. 1993,14,637641. [ 1481 K. Morihara, M. Kurokawa, Y. Kamata, T. Shimada, J. Chem SOC.,Chem. Commun. 1992, 358-360. [149] J. D. Stewart, L. J. Liotta, S. J. Benkovic, Acc. Chem. Res. 1993.26, 396-404. [ 1501 G. Wulff, D. Kasper, unpublished results; D. Kasper, PhD Thesis, University of Diisseldorf, 1999.

Rejerences [ 15 I] K. Shiraishi, G. Wulff, unpublished results.

73

[I521 J.-M. Kim, K.-D. Ahn, G. Wulff, J . Am. Chem. Soc., submitted. [I531 D. Kriz, M. Kempe, K. Mosbach, Sens. Actuators B 1996,33, 178-181. 11541 S. A. Piletsky, E. V. Piletskaya, T. I. Pansyuk, A. V. El’skaya, A. E. Rachhov, R. Levi, I. Karube, G. Wulff, Mucromolecules 1998,31, 2137-2140. [ 1551 E. Hedborg, F. Winquist, I. Lundstrom, L. Andersson, K. Mosbach, Sens. Actuators A 1993, 37-38, 796-799. [ 1561 S. Marx-Tibbon, I. Willner, Chem. Commun. 1994, 126 I - 1262. [ 1571 J. H. G. Steinke, I. R. Dunkin, D. C. Sherrington, Macromolecules 1996,29, 407-415. [I581 G. Wulff, in Frontiers in Biosensorics I-Fundamental Aspects (Eds.: F. W. Scheller, F. Schubert, J. Fedrowitz), Birkhauser, Basel, 1997, pp. 13-26. [ 1591 D. Kriz, 0. Ramstrom, K. Mosbach, Anal. Chem. 1997,69, A 345-349. (1601 H. Bengtsson, U. Roos, L. I. Andersson, Anal. Commun. 1997,34, 233-235. [ 1611 R. Broos, D. Tavernier, M. Anteunis, J. Chem. Ed. 1978,55,813. [I621 T. Ishizone, A. Hirao, S . Nakahama, Mucrornolecules 1989,22,2895-2901.

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

3 Templated Synthesis of Catenanes and Rotaxanes Frungisco M. Raymo, I.Fruser Stoddart

3.1 Introduction Catenanes [ 11 are molecules incorporating two or more component macrocycles, mechanically interlocked like links in a chain. Rotaxanes [ 11 are molecules which incorporate one or more macrocyclic components encircling the linear portion of a dumbbellshaped component in a manner reminiscent of an abacus. In both instances, no covalent bonds hold the components together. Rather, mechanical bonds - in most situations reinforced by noncovalent bonds - are responsible for linking the components. Dismembering a catenane or a rotaxane into its individual components can occur only if one or more covalent bonds are cleaved in the mechanically interlocked molecule. Thus, catenanes and rotaxanes (Figure 3- 1) behave as well-defined molecular compounds with properties significantly different from those of their separate components when they are isolated as individual molecular compounds in their own right. These unique features of catenanes and rotaxanes offer the possibility of designing the molecular-sized counterparts of bearings, chains, joints, machines, motors, and many other macroscopic objects composed of mechanically interlocked parts. The first catenanes and rotaxanes were constructed by either statistical [2] or directed [3] synthetic approaches. The statistical method relies 123 on the formation of small quantities of a species in which a cyclic molecule is threaded by an acyclic molecule. After experiencing appropriate covalent bond formation, these threaded species are con-

[n + 41Catenane

[n + 11Rotaxane

Figure 3-1 Schematic representations of [n + 4lcatenanes and [n + l]rotaxanes.

76

3 Templated Synthesis of Carenanes and Rotaxanes

verted into mechanically interlocked molecular compounds. However, threading of the cyclic onto the acyclic molecule is disfavored entropically and very small amounts of the threaded species are formed in the absence of any significant noncovalent bonding interactions between their components. As a result, the yields of the resulting catenanes and rotaxanes are extremely low. The directed syntheses of catenanes and rotaxanes involve [3] the multistep construction of so-called precatenanes and prerotaxanes. These precursors incorporate covalently bonded macrocyclic and acyclic components. After the cleavage of the covalent bonds holding the components together, mechanically interlocked molecules result. These multistep syntheses, however, are laborious, time-consuming, and, without exception, low-yielding overall. Fortunately, however, efficient methods for the production of complexes incorporating macrocyclic hosts threaded onto acyclic guests have become available with the advent of supramolecular chemistry [4]. Indeed, template-directed [S] synthetic approaches to mechanically interlocked molecular compounds have so far been developed that rely upon transition metal coordination [6, 71, hydrogen bonding [8, 91, hydrophobic interactions [7, lo], and donor/acceptor interactions [ 11, 121. In most of the transition metal-based-synthetic strategies, metal templates assist in the formation of catenanes or of rotaxanes and then the templates are removed without destroying the mechanically interlocked nature of the molecules. By contrast, when organic templates are used, they become an integral part of the mechanically interlocked structures and cannot be removed without extensive modification of the catenane’s or rotaxane’s constitution or redox state.

3.2 Metal-Templated Syntheses The first efficient synthesis of a [2]catenane, which was realized (Figure 3-2) in 1983 by Sauvage et al. [6, 131, relied upon the assistance of a metal template. The Strasbourg group made use of the fact that Cu+ ions coordinate tetrahedrally with phenanthroline ligands. Thus, when equimolar amounts of the phenanthroline-based diol 1, the preformed macrocycle 2, and Cu(MeCN),BF, are mixed together in solution, the threaded species 3 is obtained. Reaction of this intermediate with I[(CH2)20],(CH2)21in the presence of Cs2C03also affords the [2]catenate 4, but this time only in a yield of 42%. Similarly, when Cu(MeCN),BF, is mixed with two molar equivalents of the phenanthrolinebased diol 1in solution, the complex 5 is obtained. Its reaction with I[(CH2)20]4(CH2)21 in the presence of Cs2C03 affords the [2]catenate 4 in a yield of 27%. The interlocked structure of 4 was confirmed unequivocally by X-ray crystallography which revealed the tetrahedral coordination of the Cu+ ion by the two phenanthroline ligands. Demetallation of the [2]catenate 4 was achieved quantitatively by treating it with a large excess of KCN in aqueous acetonitrile. The solid state structure of the demetallated form of 4 revealed that the two macrocyclic components are still interlocked. However, in the absence of the Cu+ ions, the molecules adopt a completely different co-conformation [ 141 wherein the two phenanthroline ligands become positioned well away from each other in the component macrocycles.

3.2 Metal-Templated Syntheses

77

r $ ;

Cu(MeCN)4EF4

Cu(MeCN).,BF4

CH2Cb/ MeCN I DMF

MeCN / DMF

ON 1

0

OH

6

1

J

5pH Ho

HO

5

Figure 3-2 Metal-templated synthetic approaches to the [2]catenate 4.

Metal templates have also been employed [6, 151 to synthesize (Figure 3-3) phenanthroline-containing rotaxanes. The threaded species 6 is prepared by combining equimolar amounts of its cyclic and acyclic components and Cu(MeCN),BF, in solution. Reaction of 6 with 3,5-di-t-butylbenzaldehydeand 3,3'-diethyl-4,4'-dimethyl-2,2'-dipyrrylmethane in the presence of CF3COzH,followed by treatment with chloroanil and then with Zn(OAc)z H,O, affords the [2]rotaxane 7. Removal of the Cu' ions is achieved by treating a CH,Cl,/MeCN/H,O solution of the [2]rotaxane 7 with KCN. As in the case of

78

3 Templated Synthesis of Catenanes and Rotaxanes

the [2]catenate 4, an 'H-NMR spectroscopic investigation revealed that demetallation is accompanied by a co-conformational change which involves the circumrotation of the macrocyclic component through 180".Thus, in the demetallated [2]rotaxane 8, the two phenanthroline ligands are also remote from each other in the dumbbell and macrocycle components. However, complete reorganization to regenerate a co-conformation similar to that adopted by the metallated [2]rotaxane 7 occurs when the demetallated [2]rotaxane 8 is mixed with Zn(OAc), . H 2 0 in a CH,CI,/MeOH solution.

2) Chloroanil

3) Z ~ ( O A C ) ~ * H I CHPCIP ~O / MeOH

6

KCN I MeCN C H - ~ I~ H, ZO I

Figure 3-3 Metal-templated synthesis of the [2]rotaxane 8 under kinetic control.

3.3 Hydrogen Bonding-assisted Syntheses Hydrogen bonding interactions between amide groups can be employed (81 (Figure 3-4) to template the synthesis of [2]catenanes composed of mechanically interlocked macrocyclic lactams. This discovery was made independently by Hunter and by Vogtle. In Hunter's experiments, the diamine 9 was reacted [ 161 in CH2C12with the bis(acid chloride) 10 in the presence of Et,N to afford the diarnine 11. In an attempt to synthesize a macrocyclic lactam which was expected to bind p-benzoquinone, diamine 11 was reacted with bis(acid chloride) 10 under high-dilution conditions. However, in addition to the expected macrocycle, the [2]catenane 12 was also isolated, in a yield of 34%. The inter-

3.3 Hydrogen Bonding-assisted Syntheses

79

locked nature of the structure of the [2]catenane 12 was deduced initially from a detailed high-field NMR spectroscopic investigation and was confirmed, subsequently, by a single-crystal X-ray analysis, which revealed a network of hydrogen bonding interactions between the amide groups in the component macrocycles. A similar synthetic outcome was attained by Vogtle et al. [17, 181 when the diamine 9 was reacted with the bis(acid chloride) 13 under high-dilution conditions. In this instance, the [2]catenane 14 was obtained directly in a yield of 18%.The mechanism of these template-directed syntheses was unraveled [ 191 by analyzing the distribution of products for one- and two-step syntheses performed using starting components having various R groups on their 5-R-mphenylene rings (Figure 3-4). It is believed that the formation of a macrocyclic lactam is followed by the binding of an acyclic precursor inside its cavity as a result of hydrogen bond formation. The macrocyclization of the bound acyclic species between its termini interlocks mechanically the two macrocyclic lactams.

11

10

U

Figure 3-4 Hydrogen bonding-assisted syntheses of the [2]catenanes 12 and 14 under kinetic control.

A similar recognition motif has been employed by Vogtle et al. [8,20] and by Leigh et al. [21,22] in the template-directed synthesis (Figure 3-5) of [2]rotaxanes. The glycinebased compounds 15 and 16,incorporating terminal diphenylmethane stoppers, are able

3 Templated Synthesis of Catenanes and Rotaxanes

80

to template the macrocyclization to a macrocyclic lactam of an appropriate size, insofar as the Et,N-promoted reaction of isophthaloyl chloride 10 with p-xylylenediamine 17 in the presence of 15 or 16 affords [21] the [2]rotaxane 18 or 19 in yields of 30 or 28%, respectively. As a result of the presence of dual amide recognition sites at each end of the linear portion in the dumbbell-shaped component, the macrocyclic lactam can shuttle degenerately back and forth along the acyclic backbone in CDC1,. Variable-temperature ‘H-NMR spectroscopic investigations revealed that the rate of shuttling is affected by the number ( n ) of methylene groups linking the peptide units. At 298 K, the rates of shuttling are ca. 37000 and 5 200 s-’ for 18 and 19, respectively. In (CD,),SO, the amide recognition sites become highly solvated, the macrocyclic lactam resides preferentially on the central polymethylene chain of the dumbbell component, and no shuttling of the macrocycle is observed. The dependence of the shuttling motion on the polarity of the medium can be exploited to tune the rates of this dynamic process by controlling the degree of solvation of the recognition sites using appropriate mixtures of solvents.

I n -87 q 161 p 18

19

ClOC

H2N*NH2

Ph2CH-

HN

+ 17 17

n

Figure 3-5 Hydrogen bonding-assisted syntheses of the [2]rotaxanes 18 and 19 under kinetic control.

The hydrogen bond-directed assembly of a [2]catenane under thermodynamic control has been realized (Figure 3-6) by Leigh et al. [23] using a reversible ring-opening and ring-closing metathesis (RORCM) reaction. An isomeric mixture of the macrocyclic lactam 20 (0.2 M in CH2C12) and the Grubbs ruthenium carbene catalyst was stirred at

3.4 Hydrophobically Driven Syntheses

81

ambient temperature. The progress of the reaction was monitored by high-performance liquid chromatography (HPLC), which showed the gradual formation of the [2]catenane 21. When the equilibrium between the free macrocycle 20 and the interlocked species 21 was reached, the percentage of [2]catenane in solution was higher than 95%. However, diluting the solution shifted the equilibrium toward the free macrocycle, demonstrating that this reaction is one which is truly occurring under thermodynamic control.

Figure 3-6 Hydrogen bonding-assisted synthesis of the [2]catenane 21 under thermodynamic

control.

3.4 Hydrophobically Driven Syntheses In aqueous solution, cyclodextrins bind [ 101 organic guests inside their cavities with pseudorotaxane geometries. Thus, if the binding event is followed by the intramolecular linking of the termini of the threaded guest, mechanical interlocking of the two components occurs, yielding a [2]catenane. As a result of reasoning along these lines, Luttringhaus et al. [24] attempted unsuccessfully, as early as 1958, to synthesize a cyclodextrin-containing [2]catenane. By combining a-cyclodextrin with a 1,4-dioxybenzenecontaining dithiol in H,O, a 1:1 complex was indeed obtained. However, the oxidation of the terminal thiol groups of the guest to afford a macrocyclic disulfide did not occur. It was some 35 years later that the first cyclodextrin-containing catenane (Figure 3-7)

3 Templuted Synthesis c.f Cutenunes and Rotmanes

82

was synthesized [25] using a similar design strategy. The biphenylene-containing bisamine 22 is threaded through the cavity of the methylated Pcyclodextrin derivative 24 in aqueous solution. Thus, when the diamine 22 is reacted with terephthaloyl chloride 23 in the presence of 24 and sodium hydroxide, the [2]catenanes 25 and 26, as well as the [3]catenanes 27 and 28, are obtained, but in very low yields. It is interesting to note that the [3]catenanes 27 and 28 are topological stereoisomers and differ only in the relative orientation of the two toroidal cyclodextrin components. They were separated by reverse-phase high-performance liquid chromatography and their topologies were deduced by careful analyses of their "C-NMR spectra.

nnnn

8

0 0 0 0 NH,

22

1

uuuu

0 0 0 0 NH2

+

I

26 NaOH

23

COCl

+

H20

27

U

24

Figure 3-7 Template-directed synthesis of the cyclodextrin-containing catenanes 25-28.

The formation of pseudorotaxane complexes in aqueous solutions has also been exploited [ 101 to template the synthesis of cyclodextrin-containing rotaxanes. In the example illustrated in Figure 3-8, the diamine 29 is mixed [26,27] with a methylated acyclodextrin derivative - either 30 or 31 - in aqueous solution. In both instances, a pseudorotaxane complex self-assembles spontaneously. The subsequent covalent attachment of bulky stoppers is achieved by reacting these complexes with sodium 2,4,6-trinitrobenzenesulfonate 32. The resulting [2]rotaxanes 33 and 34 can be isolated in yields of 42 and

3.4 Hvdrouhobicallv Driven Syntheses

83

48%, respectively. The incorporation of the 2,4,6-trinitrophenyl stoppers was confirmed by the characteristic absorption band in the UV-Vis spectra of the [2]rotaxanes. Furthermore, fast atom bombardment mass spectrometry, 'H-NMR and 13C-NMR spectroscopies, elemental analysis, and the marked differences in solubilities between the [2]rotaxanes and their parent components confirmed their interlocked structures.

I $.

32

H20

NO2

02N

Figure 3-8 Template-directed synthesis of cyclodextrin-containing[2]rotaxanes33 and 34.

Fujita et al. [28] have achieved the quantitative hydrophobically driven syntheses of [2]catenanes by employing pyridine-based ligands and transition metals possessing square planar geometries. In the example illustrated in Figure 3-9, the [2]catenane 36 self-assembles quantitatively from the preformed dinuclear macrocycle 35 when heated at 100"C in a concentrated aqueous solution of NaNO,. Under these forcing conditions, the ligand-platinum bonds are constantly opening and closing. Sequential ligand exchange between the two individual dinuclear macrocycles produces an intermediate Mobius strip compound which - once again as a result of ligand exchange - is transformed into the [2]catenane 36. Presumably, strong face-to-face and edge-to-face intercomponent interactions between aromatic units within the [2]catenane drive the process thermodynamically toward the mechanically interlocked compound.

84

3 Ternplated Synthesis of Catenanes and Rotaxanes

L

36

HzN.

'NH,

U

Figure 3-9 Metal-templated synthesis of the [2]catenane 36 under thermodynamic control.

3.5 Aromatic Templates The 1,4-dioxybenzene-based macrocyclic polyether 37 binds the bipyridinium-based compound 38 as a result of [C-H-e-O] hydrogen bonding [29] between some of the polyether oxygen atoms and the a-bipyridinium protons and [n.. .n] stacking between the complementary aromatic units [30]. The same noncovalent bonds, supplemented by [C - H ... n ] interactions between the 1,4-dioxybenzene protons and the p-phenylene spacers, assist [31] in the complexation of the 1,Cdioxybenzene derivative 39 by the bipyridinium-based cyclophane 40. In both complexes - i.e., 37.38 and 39.40 shown in Figure 3-10 -the acyclic guest is inserted through the macrocyclic host with its ends protruding outside the cavity from opposite sides. This recognition motif paved [ 111 the way for the design of template-directed approaches to catenanes and rotaxanes. The first [2]catenane incorporating n-electron-rich and n-electron-deficient recognition sites was synthesized [31, 321 as outlined in Figure 3-11. The reaction of the

3.5 Aromatic Templates

85

MA

nrlnn 010 0

I Me

37.38

4pF6-

nn 0 0 OH

2PF6-

3940

Figure 3-10 The [2]pseudorotaxanes 37.38 and 39.40.

bis(pyridy1pyridinium)-containing dicationic salt 41 with the dibromide 42 produced a tricationic intermediate incorporating one bipyridinium and one pyridylpyridinium unit. Once formed, this intermediate is bound immediately by the preformed macrocyclic polyether 37,which enhances greatly the rate of the subsequent ring-closure reaction under kinetic control. After counterion exchange, the [2]catenane 43 can be isolated in a yield of 70%. A kinetic investigation of this template-directed synthesis has demonstrated [33] that the macrocyclic template accelerates the ring-closure reaction ca. 232-fold at a concentration of ca. 0.1 M. The interlocked structure of this [2]catenane was confirmed (Figure 3-1 1) by single-crystal X-ray analysis which also revealed a combination of intracatenane [C -H ...01 hydrogen bonds, [a..n] stacking, and [C -H ...a] interactions. In solution, the two mechanically interlocked rings undergo a number of co-conformational changes with respect to each other. The macrocyclic polyether circumrotates through the cavity of the tetracationic cyclophane, exchanging the “inside” and “alongside” 1,4-dioxybenzene rings. Similarly, the tetracationic cyclophane circumrotates through the cavity of the macrocyclic polyether, exchanging the “inside” and ‘“alongside” bipyridinium units. Variable-temperature ‘H-NMR spectroscopy revealed that the freeenergy barrier associated with the circumrotation of the n-electron-rich macrocyclic polyether through the cavity of the n-electron-deficient cyclophane is ca. 4 kcal mol-’ higher than that of the other circumrotation process. Interestingly, when the a-donor character of the 1,4-dioxybenzene rings is reduced by introducing fluorine substituents, the intracatenane noncovalent bonding interactions are weakened [34] significantly and, as a result, the free-energy barriers associated with the circumrotation processes decrease substantially, i.e., by ca. 3 kcal mol-’. Consistently, when better n-donors (e.g., 1,5-dioxynaphthalene ring systems) are used in place of the 1,4-dioxybenzene rings, the intracatenane noncovalent bonding interactions are reinforced [35] and the free-energy barriers associated with the circumrotation processes increase significantly, i.e., by ca 2 kcal mol-’. It is interesting to note that the n-donor character of the n-electron-rich recognition sites also affects [34, 351 the efficiency of the template-directed syntheses. Thus, when the n-donor character is diminished by introducing electron-withdrawing

-

3 Templated Synthesis of Catenanes and Rotaxanes

86

42

+

1) MeCN

2) NH4PFe I H20

Figure 3-11 Template-directed synthesis of the [2]catenane 43 under kinetic control.

substituents (e.g., fluorine atoms), the yields of the resulting [2]catenanes drop significantly to a point where it becomes impossible to obtain the catenane. By contrast, when the n-donor character is enhanced (e.g., using 1,5dioxynaphthalene ring systems), the yields increase to more than 80%in the best cases. This synthetic strategy has been extended [ 11, 361 to the template-directed synthesis of catenanes incorporating more than two mechanically interlocked components. Indeed, by enlarging the cavities of the n-electron-rich and of the n-electron-deficient ring components, as many as seven macrocycles have been interlocked. Reaction of the bis(pyridy1pyridinium)-containingdicationic salt 44 with the dibromide 45 in the presence of the macrocyclic polyether 46 affords [37] (Figure 3-12) the [3]catenane 47 in a yield of 10%. This [3]catenane incorporates two macrocyclic polyethers which are large enough to accommodate one more bipyridinium unit in each of their cavities. Thus, when the bis(pyridy1pyridinium)-containing dicationic salt 41 is reacted with the dibromide 42 at ambient temperature and pressure in the presence of the [3]catenane 47, the [5]catenane (Olympiadane) 48 is obtained, along with a [4]catenane (not shown in Figure 3-12) in yields of 5 and 31%, respectively. When the same reaction is performed under high pressure (12 kbar) conditions, the [7]catenane 49, a [6]catenane (not shown in Figure 3-12), and Olympiadane (48) are obtained in yields of 26, 28, and 30%, respectively. These [nlcatenanes were characterized by liquid secondary ion mass spectrometry which revealed peaks for [M-nPF6]+corresponding to the loss of hexafluorophosphate countenons. Their interlocked structures were demonstrated unequivocally by single-crystal X-ray analyses. These studies revealed that the [n.. . n] stacking interactions between the

3.5 Aromatic Templates

87

Figure 3-12 Conversion of the [3]catenane 47 into the [5]catenane 48 and into the [7]catenane 49.

ndonors and nacceptors are accompanied by [C-H.. .O] hydrogen bonds between the a-bipyridinium hydrogen atoms and some of the polyether oxygen atoms, as well as by [C-H- ..k]interactions between some of the 1,5-dioxynaphthalene hydrogen atoms and the phenylene rings in the tetracationic cyclophane components. The combination of noncovalent bonding interactions with the binding of bipyridinium recognition sites by melectron-rich macrocyclic polyethers was also employed [ 111 to synthesize rotaxanes under template control. In the example illustrated in Figure 3-13, the reaction of the bis(pyridy1pyridinium)-containing dicationic salt 41 with the chloride 50 affords [38, 391 a tricationic intermediate (not shown in Figure 3- 13) incorporating one bipyridinium and one pyridylpyridinium unit. This intermediate is bound immediately by the preformed macrocyclic polyether 37 and, after the covalent attachment of a second tetraarylmethane-based stopper at the other end of the acyclic components, the [2]rotaxane 51 is obtained in a yield of 18%. In solution, the macrocyclic component “shuttles” from one bipyridinium recognition site to the other. Variable-temperature ‘HNMR spectroscopy showed that this degenerate site exchange process occurs at a rate of ca. 300000 s-’ in (CD&CO at 25 “C.

88

3 Terndated Svnthesis of Catenanes and Rotaxanes

Figure 3-13 Template-directed synthesis of the [2]rotaxane 51 under kinetic control.

An alternative approach that is entirely thermodynamically controlled has also been developed [38b, 401 for the template-directed synthesis of [2]rotaxanes incorporating bipyridinium-based dumbbell-shaped components encircled by n-electron-rich macrocyclic polyethers. In this instance, a preformed macrocyclic polyether is combined with a preformed dumbbell-shaped compound. If size complementarity between the macrocycle’s cavity and the dumbbell’s stoppers is achieved, slippage of the macrocyclic component over the stoppers of the dumbbell-shaped compound occurs upon heating. Thus, when an MeCN solution of the macrocyclic polyether 37 and any one of the dumbbell-shaped compounds 52-54 is heated [38b, 4Oal (Figure 3-14) at 50°C for 10 days, the corresponding [2]rotaxanes 56-58 are obtained in yields of 52,45, and 47%, respectively. However, when the dumbbell-shaped compound 55 incorporating bis(4-t-butylphenyl)-4-isopropylphenylmethyl-basedstoppers is employed, under otherwise identical conditions, no rotaxane corresponding to structure 59 can be isolated. The replacement of ethyl groups with isopropyl groups is sufficient to prevent the slippage of the macrocycle over the tetraarylmethane-based stoppers. The mechanism associated with the passage of the macrocyclic component over the tetraarylmethane-based stoppers has been investigated [41] computationally in order to gain further insight into such an “all-ornothing” substituent effect. Model stoppers incorporating a methoxy group instead of the acyclic portion of the dumbbell-shaped compound were oriented relative to the macrocycle as illustrated in Figure 3-15. The distances D were varied stepwise from 58.0 to 35.0 A, while the coordinates of the oxygen atom of the stopper, and those of a reference point located at a distance of 60.0 A, were fixed. At each step, the superstructure was subjected to molecular dynamics at a simulated temperature of 500 K and then the energies of 200 randomly selected co-conformers were minimized. The energies calculated for the lowest energy point obtained for each step were plotted (Figure 3-16) against D.

3.5 Aromatic Templates

89

2PF6-

A

54 Et

55 i-Pr

47

0

58

59

2PFB

Figure 3-14 Syntheses of the [2]rotaxanes 5 6 5 8 by slippage under thermodynamic control.

* Figure 3-15 Initial geometries and constraints used for simulating the slippage processes.

3 Ternplated Synthesis of Catenanes and Rotaxanes

90 4030 -

I 0 -E

h 7

-

2010-

(II

0

Y

Lu

d

0-10-

-20 ! 60

I

55

I

50

D (4

45

I

40

1

35

Figure 3-16 Energy profiles associated with the slippage of the macrocycle 37 over the stoppers of 52 and 55.

This simulation protocol was employed to study the slippage processes associated with R equal to H, Me, Et, and i-Pr. In all cases, the resulting energy profiles displayed two energy barriers. The first of these is associated with the slippage of one of the polyether chains over the R group, while the second one corresponds to the slippage of the other polyether chain over one of the two t-Bu groups. When the size of the R group is increased, the first energy barrier rises, whereas the second one remains constant. When R is equal to either H or Me, the second energy barrier is rate determining. On the other hand, when R is equivalent to either Et or LPr, the first energy barrier is rate-determining. However, the energy barrier observed for slippage of the macrocycle over the i-Prbearing stopper is more than 20 kcal mol-' higher than for any of its smaller congeners. Figure 3-16 shows the plots of the energy profiles associated with R equal to H and i-Pr. It is interesting to note that the first energy barrier increases significantly and becomes rate-determining when R is i-Pr. Aromatic templates, in conjunction with coordinative bonds, have been employed by Sanders et al. [42] to self-assemble a [2]catenane incorporating a chiral metallomacrocycle. The 1,5-loxynaphthalene-basedmacrocyclic polyether 60 threads onto the a-electron-deficient compound 61 in MeCN. Thus, when both compounds and Zn(OS02CF3), are mixed in this solvent, threading of 60 onto 61 is followed by the [2 + 21 assembly of a helical metallomacrocycle as a result of the tetrahedral coordination of two Zn2+centers by the bipyridine ligands appended to the a-electron-deficient recognition sites. The resulting [2]catenane 62 was characterized by a combination of 'H-NMR spectroscopy and electrospray mass spectrometry.

3.6 Diulkylurnmoniurn-contuiningRotaxanes

91

Figure 3-17 Template-directed synthesis of the [2]catenane 62 under thermodynamic control.

3.6 Dialkylammonium-containing Rotaxanes The macrocyclic polyether 64 binds (Figure 3- 18) the dialkylammonium salt 63 with pseudorotaxane geometry in solution and in the solid state [43]. The formation of the complex 63-64is determined by [N+-H...O] and [C-H...O] hydrogen bonds between the hydrogen atoms of the ammonium center and of the two adjacent methylene groups, respectively, and the polyether oxygen atoms, as well as by [ w-..w] stacking between the aromatic units of host and guest. By enlarging the size of the host, two, three, and four dialkylammonium guests can be complexed inside the macrocyclic cavity. Thus, the [3]pseudorotaxane (63)2.37,the [4]pseudorotaxane (63),. 65, and the [5]pseudorotaxane (63)4.66 self-assemble [44]spontaneously when the dialkylammonium salt 63 is combined with the corresponding macrocyclic host. The threading of a dialkylammonium salt through the cavity of a crown ether was exploited [45] to synthesize (Figure 3- 19) a [2]rotaxane after the covalent attachment under kinetic control of bulky groups at both ends of the guest. Upon mixing the crown ether 64 with the dialkylammonium salt 67 in CH,Cl,, a [2]pseudorotaxane forms spontaneously. The a i d e groups at the termini of its guest component are capable of undergoing cycloadditions under relatively mild conditions. Thus, reaction with di-t-butyl acetylenedicarboxylate converts the [2]pseudorotaxane intermediate into the [2]rotaxane 68 in a yield of 31% as a result of the formation of trisubstituted triazole stoppers. This strategy was extended [46] (Figure 3-20) to the template-directed synthesis of a [2]rotaxane incorporating a dumbbell-shaped component possessing one ammonium and

3 Templated Synthesis of Catenanes and Rotaxanes

92

(6313.65

(63)4.66

Figure 3-18 The [n]pseudorotaxanes63.64,(63),.37, (63),.65, and (63)4.66.

67

d

Figure 3-19 Template-directed synthesis of the [2]rotaxane 68 under kinetic control.

3.6 Dialkylamrnoniurn-containingRotaxanes

93

Figure 3-20 Template-directed synthesis of the [2]rotaxane 70 under kinetic control.

one bipyridinium recognition site. Threading of the macrocyclic polyether 64 onto the dicationic salt 69, which has one stopper already attached to one of its two ends, occurs spontaneously in CHCl, at ambient temperature. Subsequent addition of 3,5-di-r-butylbenzyl bromide, and heating the solution under reflux for four days, afforded the [2]rotaxane 70 in a yield of 38%. The *H-NMR spectrum of the [2]rotaxane 70 in (CD,),CO at room temperature showed the selective binding of the ammonium recognition site by the macrocyclic polyether. However, addition of i-Pr,NEt deprotonates the ammonium group, “switching off’ its recognition properties. As a result, the macrocyclic polyether component moves and occupies the bipyridinium recognition site. The outcome is the appearance of a red color associated with the charge-transfer interactions between the catechol rings and the bipyridinium unit. Addition of CF,CO2H regenerates the ammonium recognition site, resulting in the disappearance of the red color, since the macrocyclic polyether component moves back onto the ammonium recognition site. The [2]rotaxane 70 is a remarkable example of a “clean” on/off molecular-sized switch [47] which can be operated reversibly by external stimuli. The guest component of the supramolecular complex 63-64(Figure 3- 18) incorporates phenyl rings at its two ends. These groups are small enough to penetrate the macrocyclic cavity of the host but they are not large enough to prevent dethreading. Thus, a thermodynamic equilibrium between complexed and uncomplexed species is established in solution. By contrast, the dialkylammonium salt 71 incorporates terminal groups which are slightly bulkier. Indeed, heating for several days is required [48] (Figure 3-21) to permit the threading of the host 62 onto the guest 71. After cooling the solution to ambient temperature, the threaded species 72 becomes kinetically stable and can be isolated after chromatography in a yield of >90%.Furthermore, no dissociation of 72 into

94

3 Templated Synthesis of Catenanes and Rotaxanes

Figure 3-21 Reversible complexation of the salt 71 by the macrocyclic polyether 64.

its separate components was observed at ambient temperature in a CDCI,/CD,CN (3 : 1) solution, even after several weeks. Interestingly, however, when (CD&3O is employed instead as the solvent, the quantitative dissociation of 72 into 64 and 71 occurs at ambient temperature in only 18 h, presumably since the intercomponent hydrogen bonds are destroyed in this highly solvating medium.

Figure 3-22 Complexation of the salts 73-76 by the macrocyclic polyether 64.

3.8 Exverimental Procedures

95

A similar approach has been employed (Figure 3-22) by Loeb and Wisner [49] to selfassemble [2]pseudorotaxanes composed of 1,2-bis(pyridinium)ethane axles and crown ether wheels. Indeed, by mixing any of the bis(pyridinium)-based dicationic guests 73-76 with the macrocyclic polyether 64, pseudorotaxane complexes self-assemble in MeCN. Threading of the macrocyclic components onto the dicationic guests was confirmed by the X-ray crystallographic analyses of some of these complexes which revealed the presence of [C -H ...01 hydrogen bonds between the pyridinium hydrogen atoms in the a-position with respect to the nitrogen atoms and the polyether oxygen atoms.

3.7 Conclusions Mechanically interlocked molecular compounds - namely, catenanes and rotaxanes can now be synthesized efficiently by relying on the assistance of inorganic or organic templates. These templates can guide the covalent synthesis of catenanes and rotaxanes under either kinetic or thermodynamic control. In the first instance, the irreversible formation of one or more covalent bonds determines the outcome of the overall process, i.e., it depends upon the relative stabilities of transition states leading to products. In the second case, reversible bonding interactions guide the outcome of the template-directed synthesis according to the relative stabilities of the products. When organic templates are employed, the formation of intermediate complexes is stabilized by noncovalent bonding interactions. These supramolecular intermediates are converted into mechanically interlocked molecules after the formation of either “dynamic” or “static” covalentkoordinative bonds. In both instances, the template becomes an integral part of the final product and cannot be removed without destroying its mechanically interlocked structure. When metal templates are used, intermediate complexes are formed as a result of metal coordination. Once again, the conversion of such intermediates into mechanically interlocked products requires the formation of either “dynamic” or “static” covalent/coordinative bonds. However, in some instances, the metal template can be easily removed once the mechanically interlocked structure has been assembled. These efficient template-directed syntheses not only offer the opportunity of reproducing the features of mechanical interlocking at the molecular level, but they also pave the way for the construction of molecular-level switches, motors, and machines [50].The reason is that the information used to template their formation lives on in the molecules thereafter.

3.8 Experimental Procedures 3.8.1

[2]Catenane 4 [13]

A solution of Cu(MeCN)4BF4(1.8 mmol) in degassed MeCN (30 mL) was added to a solution of 1 (3.0 mmol) in degassed Dh4F (20 mL). The mixture was stirred for 1 h at ambient

96

3 Ternplated Synthesis of Catenanes and Rotaxanes

temperature and under an atmosphere of Ar. The solvent was evaporated under reduced pressure to afford 5 quantitatively. A solution of 5 (1.5 mmol) and I[(CHz)O],(CH,)zI (3.3 mmol) in DMF (200 mL) was added dropwise over 20 h to a suspension of Cs,CO, (9.20 mmol) in DMF (400 mL) maintained at 60°C. Another portion of I[(CH2)O],(CHz)zI (1.2 mmol) in DMF (50 mL) was added over 20 h and the resulting mixture was stirred for a further 24 h at 60°C. After cooling down to ambient temperature, the solvent was removed under reduced pressure and the residue was partitioned between H 2 0 and CH2Cl,. The aqueous layer was extracted with CHzCl, (3 x 100 mL). The organic layers were combined, and HBF, (34%, 100 mL) was added. The mixture was stirred for 12 h at ambient temperature. After decantation, the solution was washed with H,O (2 x 100 mL) and a large excess of NaBF,, dissolved in the minimum amount of H20, was added. After 3 h, the organic layer was washed with HzO (2 x 100 mL) and dried (MgSO,). The solvent was removed under reduced pressure and the residue was purified by column chromatography (Si02, CH2C12)to afford the [2]catenane 4 (42%).

3.8.2 [2]Catenane 12 [16] A solution of diamine 9 (1.3 mmol) and Et,N (0.4 mL) in dry CH2Cl, (250 mL) and a solution of isophthaloyl chloride 10 (1.8 g) in dry CH2CI2(250 mL) were added simultaneously over 4 h to dry CH2C12(1200 mL) from two separate dropping funnels. The mixture was stirred for 12 h at ambient temperature. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (SO2, CHCl,). After crystallization from CHC1,-pentane, the [2]catenane 12 (34%) was obtained.

3.8.3 [2]Catenane 43 [31] A solution of the macrocyclic polyether 37 (0.18 mmol), the salt 41 (0.07 mmol), and the dibromide 42 (0.07 mmol) in dry MeCN (3 mL) was stirred for 14 days at ambient temperature. The solvent was removed under reduced pressure and the resulting solid residue was purified by column chromatography [SO,, M e O H - 2 ~ NH4CI-MeN0, (7:2: I)] to afford a red solid which was dissolved in H 2 0 (60 mL). After the addition of a saturated aqueous solution of NH,PF6, the [2]catenane 43 (70%) precipitated out of solution.

3.8.4

[2]Rotaxane 51 1381

A solution of the macrocyclic polyether 37 (0.22 mmol), the salt 41 (0.20 mmol), and the chloride 50 (0.43 mmol) in dry DMF (8 mL) was subjected to a pressure of 12 kbar for two days at 30 "C. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography [SO,, MeOH-CH,C12-CH,N0,-2~ NH,CI (70 : 16 : 9 : 5 ) ] to give a red solid which was dissolved in H 2 0 (60 mL). After the addi-

References

97

tion of a saturated aqueous solution of NH,PF,, the [2]rotaxane 51 (18%) precipitated out of solution.

3.8.5 [2]Rotaxane 56 [38] A solution of the macrocyclic polyether 37 (0.28 mmol) and the salt 52 (0.07 mmol) in MeCN (7 mL) was stirred for 10 days at 50°C. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography [SiO,, MeOH- MeNO2-CH2CI2 (6 : 1 : l)] to give 56 (52%).

3.8.6

[2]Rotaxane 68 [45]

A solution of the macrocyclic polyether 64 (0.662 mmol), the salt 67 (0.221 mmol), and di-t-butyl acetylenedicarboxylate ( I 86 ymol) in CH,CI, ( 1 0 mL) was heated under reflux for nine days. After cooling to ambient temperature, the solvent was removed under reduced pressure and the residue was purified by column chromatography [SiO,, CH2C12-MeOH (from 100: 0 to 90: lo)] to afford the [2]rotaxane 68 (31%).

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(a) P. R. Ashton, E. J. T. Chrystal, P. T. Glink, S. Menzer, C. Schiavo, J. F. Stoddart, P. A. Tasker, D. J. Williams, Angew Chem., Int. Ed. Engl. 1995.34, 1869-1871. (b) M. C. T. Fyfe, P. T. Glink, S. Menzer, J. F. Stoddart, A. J. P. White, D. J. Williams, Angew. Chem., fnt. Ed. EngI. 1997,36,2068-2070. (c) P. R. Ashton, M. C. T. Fyfe, P. T. Glink, S. Menzer, J. F. Stoddart, A. J. P. White, D. J. Williams, J. Am. Chem. Soc. 1997, 119, 12514- 12524. P. R. Ashton, P. T. Glink, J. F. Stoddart, P. A. Tasker, A. J. P. White, D. J. Williams, Chem. EUKJ. 1996,2,729-736. M.-V. Martinez-Diaz, N. Spencer, J. F. Stoddart, Angew. Chem., Int. Ed. Engl. 1997, 36, 1904- 1 907. For examples of mechanically interlocked molecules behaving as molecular switches, see: (a) A. Livoreil, C. 0. Dietrich-Buchecker, J.-P. Sauvage, J. Am. Chem. Soc. 1994, 116, 9399-9400. (b) D. B. Amabilino, C. 0.Dietrich-Buchecker, A. Livoreil, L. Perez-Garcia, J.P. Sauvage, J. F. Stoddart, J. Am. Chem. SOC.1996,118,3905-3913. (c) D. J. Cirdenas, A. Livoreil, J.-P. Sauvage, J. Am. Chem. Soc. 1996, 118, 11980-11981. (d) F. Baumann, A. Livoreil, W. Kaim, J.-P. Sauvage, Chem. Commun. 1997, 35-36. (e) A. Livoreil, J.-P. Sauvage, N. Armaroli, V. Balzani, L. Flamigni, B. Ventura, J. Am. Chem. Soc. 1997, 119, 12114-12124. (f) A. C. Benniston, A. Harriman, Angew. Chem., Int. Ed. Engl. 1993, 32, 1459-1461. (8) A. C. Benniston, A. Harriman, D. Philp, J. F. Stoddart, J. Am. Chem. Soc. 1993, 115, 5298-5299. (h) A. C. Benniston, A. Harriman, V. M. Lynch, Tetrahedron L.etf, 1994, 35, 1473-1476. (i) A. C. Benniston, A. Hamman, V. M. Lynch, J. Am. Chem. Soc. 1995,117,5275-.5291. (i) A. C. Benniston, Chem. SOC.Rev. 1996,25,427-435. (k) A. C. Benniston, A. Harriman, D. S. Yufit, Angew. Chem.. Int. Ed. Engl. 1997,36,2356-2358. (1) R. Ballardini, V. Balzani, M. T. Gandolfi, L. Prodi, M. Venturi, D. Philp, H. G. Ricketts, J. F. Stoddart, Angew. Chem., Int. Ed. Engl. 1993,32, 1301-1303. (m) P. R. Ashton, R. Ballardini, V. Balzani, A. Credi, M. T. Gandolfi, S. Menzer, L. Pkrez-Garcia, L. Prodi, J. F. Stoddart, M.Venturi, A. J. P. White, D. J. Williams, J. Am. Chem. SOC.1995,117,11171-11197. (n) R. Ballardini, V. Balzani, A. Credi, M. T. Gandolfi, S. J. Langford, S. Menzer, L. Prodi, J. F, Stoddart, M. Venturi, D. J. Williams, Angew. Chem., fnt. Ed. Engl. 1996,35,978-981. (0)P. R. Ashton, R. Ballardini, V. Balzani, S. E. Boyd,A. Credi, M. T. Gandolfi, M. Gbmez-L6pez, S. Iqbal, D. Philp, J. A. Preece, L. Prodi, H. G. Ricketts, J. F. Stoddart, M. S. Tolley, M. Venturi, A. J. P. White, D. J. Williams, Chem. Eur J. 1997,3, 152-170. (p) P. L. Anelli, M. Asakawa, P. R. Ashton, R. A. Bissell, G. Clavier, R. GBrski, A. E. Kaifer, S. J. Langford, G. Mattersteig, S. Menzer, D. Philp, A. M. Z. Slawin, N. Spencer, J. F. Stoddart, M. S. Tolley, D. J. Williams, Chem. Eur: J. 1997,3, 1113-1135. (9) M. Asakawa, P. R. Ashton, V. Balzani, A. Credi, G. Mattersteig, 0. A. Matthews, M. Montalti, N. Spencer, J. F. Stoddart, M. Venturi, Chem. EUKJ. 1997, 3, 1992-1996. (r) A. Credi, V. Balzani, S. J. Langford, J. F. Stoddart, J. Am. Chem. SOC. 1997, 119, 2679-2681. ( s ) P. R. Ashton, R. Ballardini, V. Balzani, M. Gbmez-Mpez, S. E. Lawrence, M. V. Martinez-Diaz, M. Montalti, A. Piersanti, L. Prodi, J. F. Stoddart, D. J. Williams, J. Am. Chem. Soc. 1997,119, 10641-10651. (t) M. Asakawa, P. R. Ashton, V. Balzani, A. Credi, C. Hamers, G. Mattersteig, M. Montalti, A. N. Shipway, N. Spencer, J. F. Stoddart, M. S. Tolley, M. Venturi, A. J. P. White, D. J. Williams, Angew. Chem., lnt. Ed. Engl. 1998,37, 333-337. (u) P. R. Ashton, V. Balzani, 0. Kocian, L. Prodi, N. Spencer, J. F. Stoddart, J. Am. Chem. SOC.1998, 120, 11190-11191. (v) P. R. Ashton, R. Ballardini, V. Balzani, I. Baxter, A. Credi, M. C. T. Fyfe, M. T. Gandolfi, M. G6mezLbpez, M.-V. Martinez-Diaz, A. Piersanti, N. Spencer, J. F. Stoddart, M. Venturi, A. J. P. White, D. J. Williams, J. Am. Chem. SOC.1998,120, 11932-11942. (w) M. Asakawa, P. R. Ashton, V. Balzani, C. L. Brown, A. Credi, 0.A. Matthews, S. P. Newton, F. M. Raymo, A. N. Shipway, N. Spencer, A. Quick, J. F. Stoddart, A. J. P. White, D. J. Williams, Chem. EUK

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3 Templated Synthesis of Catenanes and Rotaxanes

J. 1999,5,860-875. (y) M. Asakawa, P. R. Ashton, V. Balzani, S. E. Boyd, A. Credi, G. Mattersteig, s. Menzer, M. Montalti, F. M. Raymo, C. Rufilli, J. F. Stoddart, M. Venturi, D. J. Williams, Eu,: J. Org. Chem. 1999, 985-994. (z) N. Armaroli, V. Balzani, J.-P. Collin, P. Gaviiia, J.-P. Sauvage, B. Ventura, J. Am. Chem. SOC.1999,121,4397-4408. [48] P. R. Ashton, I. Baxter, M. C. T. Fyfe, F. M. Raymo, N. Spencer, J. F. Stoddart, A. J. P. White, D. J. Williams, J. Am. Chem. SOC.1998,120, 2297-2307. [49] (a) S. J. Loeb, J. A. Wisner, Angew. Chem. Int. Ed. Engl. 1998,37,2838-2840. (b) S. J. Loeb, J. A. Wisner, Chem. Commun. 1998,2757-2758. [50] (a) J.-C. Chambron, J.-P. Sauvage, Chem. Eur. J. 1998,4,1362- 1366. (b) J.-P. Sauvage, Acc. Chem. Res. 1999, 32, 62-71. (c) V. Balzani, M. Gbmez-Lbpez, J. F. Stoddart, Acc. Chem. Res. 1998, 31, 405-414. (d) P. R. Ashton, V. Balzani, J. Becher, A. Credi, M. C. T. Fyfe, G. Mattersteig, S. Menzer, M. B. Nielsen, F. M. Raymo, J. F. Stoddart, M. Venturi, A. J. P. White, D. J. Williams, J. Am. Chem. SOC.1999,121,3951-3957. (e) M. Venturi, A. Credi, V. Balzani, Coord. Chem. Rev. 1999,185- 186,233-256.

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

4 Templated Synthesis of Carceplexes, Hemicarceplexes,and Capsules Darren Make@ John C. Sherman

4.1 Introduction The role of templating has been found in a myriad of chemical processes and is especially important in biological systems. The most remarkable example, perhaps, is DNA replication, where a single strand of DNA templates the formation of a complementary strand through the assembly of nucleotide bases. Outside biological systems, templates play integral roles in the formation of crown ethers [ 11, catenanes and rotaxanes [2, 31 (Chapter 3), molecularly imprinted polymers [4](Chapter 2), zeolites [ 5 ] , polyporphyrins [6] (Chapter I), and other large-ring systems [7]. Thus, the role of templating is invaluable to the field of supramolecular chemistry [ 1b, 81, where chemical synthesis of complex structures is not limited by classical approaches that strictly involve covalent bond formation. Templates aid the efficient assembly of multiple components into a particular geometry through the use of non-covalent interactions such as hydrogen bonding, w-stacking, and van der Waals attractions. The word template has been described by Busch as a chemical entity that “organizes an assembly of atoms, with respect to one or more geometric loci, in order to achieve a particular linking of the atoms” [9]. In this chapter, we discuss recent research that fits this definition nicely, and focuses on the use of templating in the synthesis of the host-guest systems known as carceplexes [lo], hemicarceplexes [lo], and molecular capsules [ 111. Donald J. Cram created the field of carceplexes and hemicarceplexes [ 101. Carceplexes are defined as globe-shaped molecules that permanently entrap smaller guest molecules within their confines [ lo]. Consequently, the incarcerated guest cannot escape without breaking covalent bonds [101. Hemicarceplexes are closely related to carceplexes as both can contain molecules within their interiors. However, hemicarceplexes contain portals through which the entrapped guest can exit, given the appropriate conditions [lo]. Carcerands and hemicarcerands are analogous to the above, consisting of the corresponding host shell containing no entrapped guest [ 101. Capsules are reversible assemblies formed in solution consisting of closed-off spheroid cavities capable of encapsulating guests while excluding the solvent. The presence of a suitable template appears to be required for the formation of carceplexes, and sometimes for the formation of hemicarceplexes and molecular capsules.

106

4.2

4 Ternplated Synthesis of Carceplexes, Hernicarceplexes, and Capsules

Carceplexes

4.2.1 The First Soluble Carceplex Cram reported the preparation of the first soluble carceplex, carceplex 2. guest, from the shell closure reaction between two bowl-shaped tetrol molecules l a , base, and four molecules of bromochloromethane under conditions of high dilution in dipolar, aprotic solvents (Scheme 4-1) [12, 131.

K2c03

BrCH2CI

R w R

R R

or

or

'

R

la Ib

or R'

a, R= R'= CH2CH2C,H5 b, R= R = CH3

c, R= CH2CH2C6H,, R = CH3

Saoguest Sboguest

Scheme 4-1 Synthesis of the first soluble carceplex 2. guest.

Product yields as high as 87% have been achieved for formation of carceplex 2a.guest

[14]. These yields are remarkably high for a reaction that joins seven molecules and

makes eight new covalent bonds. Regarding templating, no carceplex or carcerand products were observed in the reaction mixture when it was conducted using the solvent Nformylpiperidine (NFP),a molecule too big for the interior of carcerand 2 a [13]. However, when the reaction was repeated doping the NFP solvent with 5%N,N-dimethylacetamide (DMA), carceplex 2a.DMA was obtained in 10% yield, which suggests that the formation of carceplex 2a.guest requires a template such as DMA [13]. 4.2.1.1

Template ratios in the formation of a n acetal-bridged carceplex

Further investigation in our laboratories led to the discovery of a one million-fold range in selectivity for various small molecules found to be suitable guests (Table 4-1) [14]. Template ratios were calculated from direct competition experiments between pairs of guests through measurement of the carceplex product ratios obtained from integration of bound guest 'H-NMR signals in the product mixtures. Just as product ratios reflect relative rates of rate-determining steps in irreversible reactions, template ratios reflect the

4.2 Carceulexes

107

Table 4-1 Template ratios for the formation of aceta-bridged carceplex 2.guest Guest

Template ratio

Pyrazine Methyl acetate 1,4-Dioxane Dimethyl sulfide Ethyl methyl sulfide Dimethyl carbonate DMSO 1,3-Dioxolane 2-Butanone Pyridine Dimethyl sulfone 1,4-Thioxane 2,3-Dihydrofuran Furan Tetrahydrofuran Pyridazine Acetone

1OOOOOO 470 000 290 000 180000

130000 73 000 70 000 38 000 37 000 34 000 19000 14 000 13000 12000 12000 8 600 6 700

1

Guest Thiophene 1,3-Dithiolane (k) 2-Butanol Benzene 2-Propanol Pyrrole Tetrahydrothiophene 1,3-Dioxane Acetamide Trioxane Acetonitrile Ethanol Ethyl acetate Diethyl ether DMA DMF NMP

Template ratio

5 800

4400

2 800 2 400 1500 1000 410 200 160 100 73 61 45 21 20 7 1

relative rates of the guest-determining step (GDS) for each of the suitable templates. The GDS refers to the step occurring along the reaction pathway during which the guest becomes permanently entrapped within the forming host [ 141. Therefore, the template effect observed is kinetic in origin. Unlike most template effects, the carceplex product is “tagged” with the template, and therefore large template ratios can be measured with good precision without the need for the determination of the rate of reaction. Yields are often compared in template studies, but these do not provide quantitative measurement of template ratios, and the range in template effects measured by yields is small. Table 4- 1 shows that pyrazine is the best template and is a million times better than the poorest measurable template, N-methyl-2-pyrrolidinone(NMP) [ 141. Also, considering the series of suitable guest molecules, the selectivity is unusually high, where small perturbations in guest structure can lead to large differences in templating abilities [ 141. For example, methyl acetate is 10000 times better than ethyl acetate [ 141. A similar template effect has also been observed in the formation of carceplex 2c-guest [15]. 4.2.1.2

Formation of a charged hydrogen bonded complex

Further investigation into the driving forces responsible for the formation of carceplex 2b.guest led to the discovery of a complex (3b-guest, Scheme 4-2) that forms in solution from two tetrol molecules (1b) in the presence of base, where a guest is reversibly encapsulated between two tetrol bowls, held together by four charged hydrogen bonds (CHBs) [ 161. Measurement of relative stabilities of complexes formed with selected guests from the series in Table 4-1 showed that complex 3b.guest expresses the same guest selectivity as carceplex 2a-guest. Thus, complex 3b.guest serves as a good tran-

108

4 Templated Synthesis of Carceplexes, Hemicarceplexes, and Capsules

sition-state model for the GDS in the formation of carceplex 2.guest [16]. Although complex 3b.guest is not at all a carceplex (it binds reversibly), it is a highly relevant model for the formation of carceplex 2a.guest. Thus, discussion of 3b.guest is presented here, rather than in Section 4.4, which deals with this type of tilled hydrogen bonded capsule.

44 DBU Guest CDC13

z=-

a, R= R'= CH2CH2C6H5 la b, R= R'= CH3 Ib c, R= CH2CH2C6H5, R'= CH,

3aoguest 3beguest 3c0guest

Scheme 4-2 Formation of hydrogen bonded complex 3 . guest.

Striking similarities are manifested in the 'H NMR spectra of 2a-c-pyrazine [14, 151 and 3b-pyrazine [16, 171, and X-ray crystal structures of carceplex 2a.pyrazine [15] and complex 3bapyrazine [ 171. These similarities, along with the guest selectivities observed for each, indicate that the same interactions are at play in driving the thermodynamic formation of 3.guest and the kinetic formation of 2.guest [17]. Favorable interactions include CHBs between the bowls, favorable van der Waals contacts, C H . - - a interactions, CH.-.X (X=O) hydrogen bonding, conjugation of 0 - H --.O- and OCH,O bonds to their respective aromatic rings, and a-.. ?rinteractions [12-171. The general trend observed experimentally was reproduced by theoretical analyses [ 181. 4.2.1.3

Mechanism of formation for an acetal-bridged carceplex

To delineate further the forces at play in forming carceplex 2a
4.2 Carcevlexes

I09

each hemisphere of the mono-bridged intermediate ultimately determines the rate at which the second bridge is installed [ 14bl. Hence, the most stable complexes (i.e., those containing the best template molecule) form the second bridge the fastest, thereby ensnaring more of the preferred guest under the given reaction conditions. The relative rates of the GDSs are largely dictated by ground-state effects, where the more stable complexes are formed in higher concentration. In other words, the rate constants for forming the second bridge are likely to be very similar for the 34 guests studied. Installations of the third and fourth bridges then ensue, providing the completed carceplex product [ 14bl. (Incidentally, the formation of the fourth bridge is the rate-determining step, but not the GDS.)

4.2.2 Large Carceplexes from Cyclic Arrays of Cavitands Knowledge gleaned in understanding the driving forces for formation of carceplex 2a.guest has benefited our research group in the desire to construct molecular hosts with larger cavities, or with multiple cavities. We have reported the synthesis of cyclic trimer 5 and tetramer 6 through reaction of A,C-bisbenzyl ether 4 with base and BrCH,CI linker (Scheme 4-3) in dimethylformamide (DMF) to render 5% and 15% yields of each,

l

I

Tetrarner 6 (15%)

Trimer 5 (5%) Base (2.5 eq) C,H,CH,Br acetone

~

"4 H

Trirner 7

H,Icat.

yo 0OH 0 OH 7

yoOH OH ' 7

2a &H

R= OCH,C,H,

a

1

H,I cat.

@OH

a

Lw Tetramer 8

Scheme 4-3 Synthesis of cyclic trimeric and tetrameric assemblies from A,C bisbenzyl ether 4. The four OH-groups in the cavitand are labelled A, B, C, D.

110

4 Templated Synthesis of Carceplexes, Hemicarceplexes, and Capsules

respectively [20]. The free hydroxyl groups of trimer 7 and tetramer 8 were obtained by hydrogenolysis [20]. Cyclic trimer 7 possesses a fairly large cavity for a synthetic host, and is conformationally very rigid. Whereas cyclic tetramer 8 has an even larger interior, its structure is far more flexible at room temperature. Sealing the upper and lower rims of these assemblies with suitable capping molecules could potentially lead to the formation of carceplexes with cavities larger than any known at present! 4.2.2.1 Synthesis of a trimer carceplex containing three DMF molecules A cap molecule of suitable size and symmetry could effectively close off the interior of trimer 7 to create a very large molecular container. Such a feat has recently been accomplished in our laboratories, where trimer carceplex 9 . 3 DMF was synthesized in 37% yield, by reaction of trimer 7 with 2,4,6-tris(bromomethyl)mesitylene under basic conditions (Scheme 4-4) [21]. No empty trimer carcerand has yet been isolated, which implies that a template (or templates) is required for formation. Can a large single template molecule form trimer carceplex 9.guest? We are currently investigating this possibility. Such an investigation begs the question: when does a template effect become a solvent effect?

DMF

KI

7

C W

9.3 DMF

Scheme 4-4 Synthesis of trimer carceplex 9 . 3 DMF.

4.2.2.2 Synthesis of a bis(carcep1ex) As in the case for cyclic trimer 7, capping of the upper and lower rims of cyclic tetramer 8 with an appropriate cap molecule could potentially render a carceplex with an unprecedentedly huge cavity. However, due to its flexible structure, tetramer 8 can fold in upon itself, forming a carceplex with two separate chambers (Scheme 4-5). Subjecting tetramer 8 to optimal carceplex-forming conditions found for 2.pyrazine effectively gave the bis(carcep1ex) 10.2 pyrazines in 74% yield [20]. MM2 calculations performed on 10.2 pyrazine suggest that the two neighboring capsules are twisted 90" with respect to each other [20]. The conformation of these two capsules and the relative positions of each guest inside could possibly lead to some kind of intercapsular communication process, which could be important in the development of molecular switching devices [20].

111

4.2 Carceplexes

BrCH,CI

K2CO3 Pyrazine, NMP

10.2 guest

8 Scheme 4-5 Synthesis of bis-carceplex 10.2 pyrazines.

4.2.3 Benzylthia-bridged Carceplex Carceplexes have also been synthesized using templates from cavitands with functionalities other than phenols. Cram synthesized benzylthia-bridged carceplex 13.guest through the shell-closure reaction between tetra(benzy1chloride) cavitand 11and tetrabenzylthiol cavitand 12 in the solvents 2-butanone, 3-pentanone, ethanolhenzene ( 1 :2), dimethylformamide (DMF), methanolhenzene (2 :l), and acetonitrilehenzene (2 :l), yielding carceplexes 13-2-butanone, 13-3-pentanone, 13.ethanol,13-DMF,1 3 - 2methanol, and 13.2 MeCN respectively (Scheme 4-6) [22]. Technically, 13.2 MeCN is a hemicarceplex, as one acetonitrile molecule was found to escape the interior of the host via a "billiard-ball" effect, leaving 13.MeCN when heated in toluene [22]. The forma-

R

R

R

R

M2C03

11

+

Guest Solvent

M= K, Cs, Rb R= CH2CH2C6H,, (CH,),CH, R

12 Scheme 4-6 Synthesis of benzylthia-bridged carceplex 13. guest.

R

R

13.guest

R

112

4 Templated Synthesis of Carceplexes, Hemicarceplexes, and Capsules

tion of carceplex 13 . guest was found to be a templated process, as indicated by the absence of any empty carcerand (13) in any of the product mixtures [ 2 2 ] . Moreover, when the reaction was conducted in an apolar solvent such as benzene, in the absence of any other potential guests, no carceplex 13 .guest was found to form [22]. However, when benzene was used as a co-solvent to help dissolve cavitands 11and 12 in the polar solvents ethanol, methanol, or acetonitrile, only carceplex 13 .guest containing a polar solvent molecule as guest was isolated. Preliminary experiments in our laboratories suggest that carceplex 13 . guest forms selectively in the presence of more than one suitable guest [23]. The range in selectivity observed was calculated to span two million-fold.

4.2.4 Calix[4]arene-Cavitand Hybrid Carceplexes All carceplexes mentioned so far have used only cavitand building blocks as their precursors. In fact, there are very few examples in the literature of carceplexes that significantly deviate from the two cavitand topology of 2-guest or 13-guest.Two examples already mentioned are 9.3 DMF and 10.2 pyrazine. Reinhoudt and co-workers have prepared asymmetric carceplexes composed of both calixarenes and cavitands [24]. The synthesis of 15.guest involved intramolecular cyclization of endo-coupled compound 14, where the t-butyldimethylsilyl (TBDMS) groups are removed in situ with CsF, followed by displacement of the chlorides with the phenoxides of the resorcinarene (Scheme 4-7) [24]. Amide and sulfoxide guests/templates were incarcerated by solvent inclusion, while other potential guests incapable of acting as the solvent were encapsulated through doped inclusion [25]. Suitable guests/templates reported are DMF, DMA, NMP, 1,5-dimethyl2-pyrrolidinone, dimethyl sulfoscide (DMSO), ethyl methyl sulfoxide, thiolane- 1 -oxide, 3-sulfolene, and 2-butanone [25]. The relative templating abilities of several guests were

H

nI

__

-. CsF, KI

cs*cos Guest

14, R= TBDMS

1%guest

Scheme 4-7 Reinhoudt’s calix[4]arene/resorc[4]arene carceplex 15. guest.

4.2 Carceplexes

113

investigated through competition reactions by adding 5 vol% of each competing guest to the reaction in 1,5-dimethyl-2-pyrrolidinonesolvent [25]. The results are displayed in Table 4-2, where DMA is the best template for the synthesis of carceplex 15.guest. The relative templating abilities of these guests were described as comparable to the association strengths between the calix[4]- and resorcin[4]arene cavity of the host and the guest [25]. DMA is a superior template as it provides the best solvation of the transition state during shell closure. Stabilization of this transition state, thus promoting formation of the resulting product, is believed to arise partly from hydrogen bonding between the NH protons of the host and the incarcerated guests [25]. Slow association between the host and guests that are poorer templates would lead to the formation of intermolecularly coupled products, and/or decomposition of the chloroacetamido groups of precursor 14 [25]. Carceplexes were not formed using the potential guest molecules N,N-dimethylthioformamide, N,N-dimethylthioacetamide, N,N-dimethylmethanesulfonamide, cyclopentanone, N-ethyl-N'-methylacetamide,and biacetal [25].Attempts at including six-membered ring molecules, and the best template in the formation of 2*guest,pyrazine, failed as well [25]. Reinhoudt's preparation of diastereomeric complexes 15.guest, each differing in the orientation of the contained guest, provided means for the discovery of a new form of stereoisomerism, carceroisomerism [26]. Application of these novel host-guest structures as molecular switches has been suggested [25,26]. Table 4-2 Template ratios and yields for the formation of Reinhoudt's carceplex 15.guest Guest

Ternplating ability"

Yield (%)b

DMA DMSO DMF 2-Butanone

100

27 16" 13' 16

63 21 21

DMA is set at 100. Isolated carceplex when only one guest is used during doped inclusion. Yield of deuterated guests.

a

4.2.5 Metal-bridged Carceplexes Carceplexes traditionally consist of neutral organic molecules imprisoned by the cowlently-linked, neutral host carcerands. Dalcanale and co-workers at the University of Parma have expanded the scope of carceplexes by characterizing carceplex 17.guest, synthesized through the metal-induced self-assembly of two molecules of tetracyanocavitand 16 connected with four Pd" or Ptrrsquare-planar linkages, where the incarcerated guest is a triflate anion, CF,SO; (Scheme 4-8)[27]. The structure of 17 -guest was confirmed through extensive characterization involving NMR ('H, 13C, ,'P, I9F) and FT-IR spectroscopies, electrospray-MS, and vapor-phase osmometry [27]. Carceplex 17b - guest was also discovered to disassemble by ligand

4 Ternplated Synthesis of Carceplexes, Hemicarceplexes, and Capsules

114

exchange upon addition of eight equivalents of triethylamine to give two molecules of precursor bowl 16 and four PtL(NEt,),(OTf), (L= 1,3-bis(diphenylphosphino)propane) [27]. Subsequently, 17. guest reforms upon addition of eight equivalents of triflic acid (CF,SO,H) [27]. Ligand exchange controls the reversible cage formation [27]. As no empty cage 17 was ever observed as a product, CF,SO; is required as a template [27]. 3+ 7 CF3 SO, CN

CN

/,oq

ML(OTf), a M= Pd, R= C,, H,, b M= Pt, R= C,, Hz3 c M = Pd, R= CeH, 3

CHZCIZ

-

k k

'

R

I

R

-

17mguest

Scheme 4-8 Dalcanale's metal-bridged cage complex 17. guest. L = 1,3-bis(diphenylphosphino)propane.

4.3 Hemicarceplexes Closely related to carceplexes are .-zmicarceplexes, for which some template studies have been undertaken. A wide range of hemicarceplexes have been synthesized to date, most of which involve the linkage of two cavitands, where a wide variety of differently sized spacers have been incorporated. Thus, fairly large-ring portals have been created in the hemicarceplex skin, which allow entrapped guest molecules to escape into the external medium.

4.3.1 Template Effects in the Formation of a Trismethylene-Bridged Hemicarceplex Template effects in the formation of hemicarceplex 19. guest (Scheme 4-9) have been investigated [28]. Very similar in structure to carceplex 2 . guest, tris-bridged 19. guest is formed by reaction of two trio1 bowls (8) with three molecules of bromochloromethane. Notice that the shell of hemicarcerand 19 has a single modest-sized hole, through which, with sufficient time and heat, the trapped guest can escape. High yields of 19. guest were obtained using templates such as pyrazine, 1,4-dioxane, DMSO, THF, acetone, pyrrole, 1,3,5-trioxane, DMA, and NMP [28]. The yields were found to surpass theoretical yields

4.3 Hemicarceplexes

115

expected from statistical analyses [28, 291. The template ratios determined for these guests in hemicarceplex 19 mirrored those for carceplex 2.guest [28]. Also, a complex similar to 3 . guest (34. guest, Figure 4-4) has been discovered to form, where two triol bowls (18) are prealigned about a guest so that the maximum number of inter-bowl hydrogen bonds (three) form [28], Non-covalent interactions between the forming host and suitable templates promote the most stable alignment of the triol bowl precursors, and thus the templates facilitate the formation of hemicarceplex 19 guest [28].

-

R

R

R

R

R

R

R

R

K2c03

'H

H'

R= CH,CH,C,H, 18

190guest

Scheme 4-9 Synthesis of tris(aceta1)-bridged hemicarceplex 19. guest.

4.3.2 Hemicarceplexes Containing Four Slotted Portals Using the same shell-closure approach as for the synthesis of carceplex 2 . guest, a large number of hemicarceplexes with differently sized portals have been formed [ 10, 301. Few template studies exist on these hemicarceplexes, as most have been prepared by Cram to investigate complexation/decomplexation behaviors and novel reactivity of the entrapped species [30]. Our research group is currently probing the template effect in the formation of hemicarceplex 20a. guest. Preliminary results feature p-xylene as the best template, which is over three thousand times better than the poorest measurable template, N-formylpiperidine [3 11. Template effects have also been observed in separate shell-closure reactions forming 20b. guest and 20c. guest (Figure 4-1). Yields of 20b guest and 20c-guest were increased from 20 and 18% to 51 and 27%, respectively, upon addition of 1,2-dimethoxybenzene to the reactants [3Og]. This is the first of two reported examples where the formation of a hemicarceplex is templated, but the product is not "tagged" with the template, as it escapes after the host is formed. Some intriguing results involving template effects in the formation of rn-xylyl-bridged hemicarceplexes (Figure 4-2) have been observed [32]. The robustness of 21 guest prompted Cram and co-workers to investigate how binding ability is changed upon altering the cavity size of the host. This was accomplished through various shell-closure reac-

-

116

4 Terndated Synthesis of Carcedexes, Hemicarcedexes. and Camules

20a*guest, x= 4, 20b*guest, x= 5, 20c*guest, x= 6

R= CH,CH,C,H,

Figure 4-1 Tris-bridged hemicarcerand 20. tions using cavitands that differ in their interhemispheric “spanners”: methylene (27a, b), ethylene (28a, b), and propylene (29a, b) (Figure 4-3) were explored [32]. Hemicarceplexes having like (21-23) and unlike (24-26) northern and southern hemispheres were prepared by two different strategies, each revealing striking differences in yields [32]. These methods were analogous to the methods used to form carceplex 2 . guest (“2 + 4” addition of two tetrol bowls and four linker molecules), and carceplex 13 .guest (“1 + 1” addition of one tetrol with one tetrachloride bowl). Applying the “2 + 4” conditions, 21 NMP was synthesized in 50% yield from tetrol 27a and linker in NMP [32]. In contrast, the “1 + 1” conditions produced only a 2.2% yield of 21 .NMP from tetrol 27a plus tetrachloride 27b [32]. These results suggest that NMP acts as a template, enabling two tetrol bowls to preassociate to form complex 3 . NMP (R = R’= C,H, ,). In the first reaction, NMP can be considered as a “positive” template, as the two preorganized tetrols react with the linker to form bridges leading to the desired product in high yield. However, NMP can be considered a “negative” template in the second reaction since the formation of the desired product is inhibited as the effective concentration of free tetrol 27a available for reaction with the tetrachloride bowl 27b is reduced in forming a dimer of 27a. In addition, installation of the first bridge would lead to a poorly aligned intermediate that would be unable to form intercavitand hydrogen bonds, and thus it would be poised for oligomerizatiodpolymerization. NMP was also found to act as a “negative” template for the syntheses of hemicarceplexes 24. guest and 25 -guest. Reaction of 28a and 27b gave a much higher product yield of 24 -guest(21%), than the corresponding reverse reaction involving 27a and 28b (2%) [32]. Similarly, 25.guest is formed in 1.8% yield from 29a and 27b, and -0% from 27a and 29b [32]. These results are consistent with 27a promoting a complex 3.NMP whereas 28a and 29a are precluded from such. As no complex akin to 3.guest forms, the tetrols are available for the “1 + 1” reaction, but are not preorganized to facilitate the “2+4” reaction. Lack of complex formation for 28a and 29a also explains the differences in the yields of 22. guest and 23. guest, between reactions involving tetrol bowl plus tetrachloride bowl (43% and 6%,respectively) and those involving tetrol bowl plus linker (8% and 0%, respectively).

Q

5. 0

<

%

R

R

21

R

R

R

R

22

R

R

R

R

26

23 R

R

L.l

P

I18

4 Templated Synthesis of Carceplexes, Hemicarceplexes, and Capsules

27

29

28

5

1 1

Figure 4-3 Cavitand building blocks used in the synthesis of hemicarceplexes 21-26.

Template effects appear to be absent in three out of four of these reactions. However, addition of 29a to 29b only gives the product 23-guest when 1,2,3-trimethoxybenzene is present in the reaction at 5% (w/w) of the solvent [32]. It was suggested that 1,2,3-trimethoxybenzene templates the formation 23 .guest, which escapes during the work-up, as only the free host 23 was isolated [32]. This is the second example where such a template/escape process occurs in the formation of hemicarceplexes (vide infra). Support for this notion is gleaned from the isolation of 25.1,2,3-trimethoxybenzenefrom the reaction of 29a and 27b. 25. guest did not form in the absence of 1,2,3-trimethoxybenzene[32].

4.4

Capsules

Rebek has defined self-assembling capsules as "receptors with enclosed cavities, formed by the reversible noncovalent interaction of two or more, not necessarily identical, subunits''[ 111. Consequently, the resulting capsule has a well-defined structure in solution, and shows binding capabilities that are absent for the individual components alone [ 111. Examples provided in this section are restricted to capsules that form only in the presence of a template. As a result, unique sets of spectroscopic data are acquired for solutions of both the individual subunits in the presence and absence of the required templates.

4.4.1

Capsules Composed of Cavitands Linked via Covalent Bonds or Charged Hydrogen Bonds

Referring back to Section 4.2.2.2, we saw that two tetrol bowls (1)can wrap themselves around a suitable template in the presence of base to form complex 3 . guest. The relative stabilities of complexes formed with several guests were found to mirror the template

4.4 Capsules

119

effect observed in the formation of carceplex 2 . guest. Further investigation into the significance of complex 3 . guest in the mechanism of carceplex formation has also led to the discovery of eight new complexes, 30-37. guest, all of which reversibly encapsulate small molecules within their cavities (Figure 4-4), and all of which manifest similar guest selectivity to 3 . guest [ 191. Thus, each of these complexes, along with complex 3 . guest, are valid transition state models for the formation of carceplex 2 . guest. Note that 30 guest, 34 guest, and 36. guest do not have CHBs (for definition, see section 4.2.1.2); thus these complexes are neutral. Moreover, 30,34, and 36 do not require a template for their formation, whereas 31, 32, 33, 35, and 37 do. Enthalpy-entropy compensation appears to be at play in the formation of capsules 3 . guest and 30-37 guest; exchange rates were calculated to range from microseconds to days, depending strongly on temperature, host, solvent, and guest [ 191. 9

-

30

31

32

33

< 34

35

36

37

Figure 4-4 Schematic representations of various self-assembling reversible capsules derived from cavitand precursors.

4.4.2 Rebek’s “Tennis Balls”, “Softballs”, and “Wiffle Balls” Rebek and co-workers have successfully prepared many fascinating self-assembling capsules. These systems are all related, as they involve the oligomerization of two or

1 20

4 Templated Synthesis of Carceplexes, Hemicarceplexes, and Capsules

more concave monomeric subunits [ I l l . Many of these subunits incorporate glycoluril functionalities at each terminus of the molecule, and contain hydrogen bond donor and acceptor groups, which are separated by a rigid spacer. These concave subunits are selfcomplementary and can dimerize to form hollow structures seamed together by numerous hydrogen bonds. In the process, cavities large enough for small molecules are created. The first report in the literature of one of these hydrogen bonded dimers, was Rebek’s “tennis ball” 38.38 (Figure 4-9,which forms in solvents that do not compete for hydrogen bonds [33].Apparently, the “tennis ball” does not require a template for its formation, as the empty dimer has been observed by ‘H-NMR [33].However, the mystery of whether or not the cavity of this species is truly empty, or contains dissolved gases, is still unanswered [33,34].

Figure 4-5 Rebek‘s “tennis ball”.

38.38

Modified versions of Rebek’s “tennis ball” have been prepared by extending the structure of the spacer between the two glycoluril termini in the monomeric subunit [35].Figure 4-6shows the various monomeric subunits (39-41) that Rebek and coworkers have used to form dimeric hydrogen-bonded capsules: 39. guest. 39,40. guest. 40, and 41 .guest ‘41.These spherically shaped, dimeric capsules are typically identified by the characteristic concentration independent downfield-shifted resonances assigned to the urea N -H protons in the ‘H-NMR spectra. In addition host-guest signal integrations are in accord with 2 : 1 complexes being formed. Monomers 39a and 39b are both insoluble in NMR solvents such CHC1, and p-xylene-d,,, where they form gel-like phases of low-order hydrogen-bonded aggregates.[351 Compound 39 rapidly dissolves upon addition of various adamantyl and ferrocene derivatives to form reversible capsules 39. guest. 39, which can dissociate and recombine slowly on the ‘H-NMR timescale [35].Typical ‘HNMR spectra also show upfield signals for encapsulated guests as well as signals for excess free guest [353. Hence, binding affinities have been quantified through measurement of equilibrium association constants for 1,3,5,7-tetramethyladamantane(6.7), 1 adamantaneamine (190), 1-adamantanecarboxamide (3 lo), 1,3-adarnantanedicarboxylic acid, and 1-ferrocene-carboxylic acid (280) [35].(Note that the values in parentheses are denoted as apparent association constants, K,(app) (in M - I ) , because of the unknown aggregation state of the “monomer”.) These guests template the formation of dimeric capsules 39 a . guest. 39a and 39 b . guest * 39 b.

4.4 Cupsules

121

x X

39

40

41

a R, = R2 = CsH5,X= H b R1 = R2 = C Oz -i-C5H , X = H c R1= R2= 4-n-heptylphenyl, X= OH d R = CO 4-C H , R = p-C H OC

39eguest.39 40.guest.40 41 egueste41

11

I

2

5

1 f

2

6

4

6

H

1 3

Figure 4-6 Rebek’s dimeric “softball” and “wiffle-ball” capsules.

Incorporating four additional hydroxyl groups in the aryl spacer gives a new monomer (39c),with improved solubility in common NMR solvents [36]. “Softball” 39c.guest. 39c is tied together by up to 16 hydrogen bonds, twice the number in 39a-guest.39a and 39b.guest. 39b [36].These additional hydrogen bonds are derived from participation by the hydroxyl groups, whose proton signals are shifted downfield in the ‘H-NMR spectra [36]. Equilibrium association constants were determined for the formation of 2 :1 host : guest complexes with adamantane (440), I-adamantanecarboxamide (2 SOO), 1-ferrocenemethanol (3 SOO), 1-adamantanecarboxylic acid (5600), 1-ferrocenecarboxylic acid (17 000), and 1-adamantanemethanol (27 000) as guests [36]. Guests that are able to form a maximum number of favorable van der Waals interactions with the interior of “softball” dimers form the most stable complexes [35, 361. Stabilities of these dimeric complexes also improve when the encapsulated guest possesses functionalities capable of participating in hydrogen bonding with the seam of the host [35,36]. Enthalpies and entropies of capsule formation were determined in CDCl,, p-xylene-d,,, and benzene& solvents [36, 371. Formation of capsules 39a.guest. 39a, 39b guest 39b, and 39c.guest. 39c is entropically driven, and is accompanied by a more modest gain in enthalpy [36, 371. This is consistent with the displacement of two solvent molecules by a single guest from the interior of these “softball” capsules [36,37]. As corroboration, three unique capsules have been observed to form when monomers 39a-c are equilibrated in an equimolar solution of benzene-d, and fluorobenzene-d5 [36, 371. Dimers containing two benzenes, two fluorobenzenes, and one of each guest were identified [36,37]. This ability to bind multiple guests in a single cavity has been exploited recently by Rebek and co-workers in the acceleration of Diels- Alder reactions within “softball” dimers [38]. +

122

4 Templated Synthesisof Carceplexes, Hemicarceplexes, and Cupsules

The structural diversity of “softball” capsules has also been analyzed by replacing the aryl spacer in the monomer with isomeric ethylene groups (shown in Figure 4-6) to form the congeners 40. guest 40 and 41. guest. 41, referred to as “wiffle” balls [39]. Various molecules were encapsulated in 40. guest. 40, but no template effects were reported [39]. Out of the five solvents tested (CD2C12,CDCl,, C6D6, toluene-d,, and p-xylened,,), heterodimer 40. guest. 41 was only observed to form in benzene-d,, which could implicate benzene as a template for 40.guest. 41 [39]. Chiral “softballs” have also been reported from symmetric (39a and 39b) and asymmetric (39d) monomers, when optically active camphor derivatives were encapsulated [40]. For example, dimerization of 39a in the presence of camphanic acid in p-xylened,, gave two sets of host resonances in the ‘H-NMR spectra [40]. Doubling of these signals is a result of the formation of two isomeric “softball” dimers in which the guest lies in two different orientations [40]. Reorientation of the guest within the intact capsule is energetically unfavorable and can only occur through a stepwise process involving dissociation, then rotation of the guest, followed by recombination [40]. Therefore, chirality is induced from within the capsule [40]. Chirality can also be introduced from an asymmetric surface (39d) provided by the host in binding camphor as in “softball” 39d.39d [40]. This is evident in the doubling observed of the guest resonances in the ‘H-NMR spectrum [40].

-

4.4.2.1 Template effects of solvent in the synthesis of “softball” dimers Softball derivatives have been prepared by coupling tetraester 42 with two equivalents of diamine hydrochloride 43 (Scheme 4-10) in a variety of solvents in the presence of Et,N [41, 421. Product mixtures were found to contain three stereoisomers: C-shaped 44, S-shaped 45, and W-shaped 46 [42]. C-shaped isomer formed in higher yields in aromatic solvents such as benzene-d,, toluene-d8, and p-xylene-d,, (dimerization of 44 has been previously observed in p-xylene-d,,) [42]. Only statistical ratios of the three isomers were obtained in CH2C12and CHCl,, which are solvents that are less suitable for dimerization [42]. The overall reaction sequence giving the C, S , and W-shaped isomers proceeds through two steps. The first involves the formation of 47 ( E ) and 48 (Z)in each of the above mentioned solvents (Figure 4-7) [42]. Products 44, 45, and 46 are then formed in the second step by formation of two more amide bonds. In the second step, suitable solvents (vide supra) template the formation of the desired C-shaped 44 from the (Z)intermediate 48, giving greater than statistical yields [42]. A zwitterionic tetrahedral intermediate resembling the structure of C-shaped 44 was proposed to be involved, whose concave surface provides a complementary fit to aromatic solvents [42]. Further stabilization of the zwitterionic intermediate directly leading to C-shaped 44 was also proposed to be provided through dimerization with another molecule of 44,with concomitant reversible encapsulation of solvent as guest [42]. However, no experimental evidence supporting this suggestion has yet been put forth.

4.4 Capsules

123

U 46 W-shaped Scheme 4-10 Synthesis of C, S, and W-shaped monomeric diglycoluril isomers 44-46.

a R= CO,dC,H,, R'= CeF6 b R= 4-(n-C&30)-C&, R'=2,4,5-C&&

Figure 4-7 (E) and (Z) intermediates

in the formation of isomeric diglycoluril functionalized monomers 44-46.

4.4.3 Other Hydrogen Bonded Capsules Rebek and co-workers have also produced self-assembling capsules where the monomer possesses C, symmetry (as opposed to C,), by incorporating multiple glycoluril moieties into a flattened aromatic surface. For example, "jelly donut" dimer 50 forms in CDC13 from monomer 49. This capsule features a flattened spherical interior cavity that can accommodate disk-shaped molecules like benzene and cyclohexane (Scheme 4-11) [43].

4 Temnlated Svnthesis of Carcevlexes. Hemicarcedexes. and Crwsules

124

= Guest n

:

-

-

"'"76"

-

\

R=

/-...,A

cw

49 Scheme 4-11 Formation of Rebek's ''jelly donut".

Recently, tetrameric assembly 52 (Scheme 4-12) has been reported [44]. Preparation of 52 involves the self-assembly of four discrete concave-shaped, monomeric subunits (51). Compound 51 exists in its monomeric state and is soluble in solvents that compete for hydrogen bonds, such as DMSO-d, [44]. In solvents such as CD,Cl,, CDCl,, C,D,, toluene-d,, and p-xylene-d,,, monomer 51 remains insoluble, existing as suspensions, which form clear solutions when adamantyl derivatives are added [44]. 'H-NMR spectra of these solutions show the characteristic downfield-shifted glycoluril N-H signals, indicative of hydrogen bonding. A 4 : 1 ratio for host :guest signals was also measured, thus distinguishing the formation of a tetrameric assembly which truly encapsulates its guests [a]. Apparent association stabilities (in M-') were reported for complexes formed with the guests adamantane-2,6-dione (3200), 2-adamantone (1 60), 1-adamantsno1 (48),bicyclo[3.3.l]nonane-2,6-dione,and adamantane (19) [MI. These values suggest that hydrogen bonding between the host with guests that contain carbonyl groups

0

Guest mesitylene-d,, 7

_____*

51a Ar= 4-n-heptylphenyl 52b Ar= 4-n-dodecylphenyl

53

Scheme 4-12 Formation of tetrameric hydrogen-bonded capsule 52.

4.4 Capsules

125

(i.e. glycouril N-H...O=CR,) increases complex stability [44]. The existence of such hydrogen bonding is evident in the 'H-NMR spectra of the corresponding capsules with guests (vide infra) [44]. Cylinder-shaped molecular capsules such as 54 (Scheme 4-13) have also been reported. Deep-cavity resorcinarene 53 was found to dimerize through a seam of eight bifurcated intermolecular hydrogen bonds between the imide and carbonyl functionalities located on the rim of the monomer [45]. Dimerization was observed to be templated in mesitylene-d,,, according to the 'H-NMR spectra, which feature downfield shifted N-H host signals upon encapsulation of guests such as bibenzyl, terphenyl, dicyclohexyl carbodiimide, truns-4-stilbene, N-phenylbenzylamine, benzyl phenyl ether, trans-4-stilbene methanol, and p-[N-@-tolyl)]toluamide [45]. Although dimer 54 does form in solvents such as CDCl,, benzene-& and toluene-d8, mesitylene-d,, itself appears to be too large for the cavity, as suggested by the presence of multiply hydrogen-bonded N-H signals in the 'H-NMR spectra [45]. Capsules do form in mesitylene-dl, upon addition of templating guests such as benzene, p-xylene, toluene, p-trifluoromethyltoluene, p-chlorotoluene, 2,5-lutidine, and p-methylbenzylalcohol, where specific pairs are preferably encapsulated over others [45]. For example, in the presence of a 1 : 1 ratio of benzene:pxylene in mesitylene-d,2, the two resorcinarenes (53)dimerize, forming capsules containing one of each guest, preferably over other identical pairs of guests [45]. It was suggested that one benzene together with one p-xylene provides the best occupancy factor [46] as two benzenes leave too much and twop-xylenes leave too little empty space [45]. u

Y

-

Guest(s)=

R= 1'

1 H23

53

54

Scheme 4-13 Formation of cylindrical-shaped capsule 54 from deep-cavity resorcinarene 53.

4.4.4 Capsules that do not Involve Hydrogen Bonding Using a similar approach to forming synthetic capsules, other structures have been designed that utilize attractive interactions between the host and the guest, other than van der Waals interactions and hydrogen bonding. One example is the formation of a capsule (56) from two equivalents of bowl-shaped Lewis acid precursor, aluminum tris(2.6-diphenylphenoxide) (ATPH) 55, with a guest such as 1,4-cyclohexanedione (Scheme 4-14)

126

4 Templated Synthesis of Carceplexes, Hemicarceulexes. and Cansules

[47]. Coordinate bonds between the aluminum center of ATPH and the carbonyls of the guest hold the two ATPH subunits together [47]. The resulting dimeric capsule renders the bound guest completely sheltered from the external environment: hence the guest does not dissociate in the presence of other carbonyl substrates [47].Addition of MeLi ( I equiv) to a solution containing capsule 56 and 4-tert-butyl- l-rnethylcyclohexanone resulted in the recovery of the diketone and 4-tert- l-methylcyclohexanol[47].The interior of capsule 56 was also found to serve as a miniature reaction chamber as Diels-Alder adducts were recovered bound when, at low temperature, two equivalents of ATPH were added to a solution containing a quinone derivative and a suitable diene [47]. Interesting regio- and stereoselective features of some of the Diels-Alder reactions were observed upon analysis of the cyclo-adduct product distributions. Results indicated that preorganization of the diene and quinone (dienophile) with ATPH prior to capsule formation is crucial [47].

‘i“

Ph+ph

ru

ri

2 YI2

VI I

W

55

I

56

Scheme 4-14 Formation of capsule 56 from Lewis acid receptor ATPH (55).

The templating of dimeric capsules incorporating porphyrins has also been reported recently. These reports describe the self-assembly of molecular capsules based on metalto-ligand interactions of two dizinc(I1) bisporphyrins around tetratopic Lewis base template guests [48, 491. The structure of the monomers used consists of two porphyrin derivatives covalently linked by a concave spacer to give molecules having a “clip-like” topology. Dimerization of two “clips” was found to occur using tetratopic aliphatic or tetrapyridylporphynn templates, yielding structures that are described as resembling a universal joint.

4.4.5

Other Capsules

Various other examples have been provided in the literature involving the formation of molecular capsules. However, guest binding by these capsules may not have been studied, or evidence of a template requirement for formation may not have been present. These include urea-based calixarene dimers [50], “deep-cavity” resorcinarenes [5 I],

References

127

cyclocholate dimers [52], calixarene heterodimers [53], cucurbituril capsules [54], cyclodextrin dimers [55], resorcinarene-based cages [56],self-assembling calix[4]resorcinarene oligomers [57], self-assembled block copolymer aggregates [ 5 8 ] , and CTV heterodimers [59].

4.5 Conclusions This chapter demonstrates the importance of templating in the formation of “molecules within molecules” in the form of carceplexes, hemicarceplexes, and self-assembling capsules. Suitable template molecules can facilitate the formation of large supramolecular structures via favorable non-covalent interactions. Selectivity for particular template molecules can range up to one million-fold. Recognizing and understanding the roles of the molecular forces involved in these processes is important if we are to understand biological assemblies further, including enzymes, cell membranes, and viruses. Information obtained in forming smaller well-defined molecular assemblies will also enable scientists to apply that knowledge in the formation of much larger supramolecular structures, eventually reaching and perhaps even surpassing the size and complexity of those found in nature. The reversible nature of self-assembling capsules has already been exploited as molecular switching devices and catalysts. Other applications may involve the development of artificial enzymes, and the design of specific drug delivery systems.

Acknowledgements We thank Christoph Naumann and Ashley Causton for careful reading of this manuscript. We also thank the funding agencies (NIH, PRF, and NSERC) for supporting our work, and we thank the authors of the references discussed for providing a stimulating area to review.

References [l] (a) C. J. Pederson, J. Am. Chem. SOC.1967, 89, 7017-7036; (b) C. J. Pederson, Aldrichim. Acta 1971, 4, 1; (c) D. J. Busch, A. L. Vance, A. G . Kolchinski, in Comprehensive Supramolecular Chemistry; J.-M. Lehn, J. L. Atwood, D. D. MacNicol; F. Vogtle, Series Eds.; Pergamon: New York, 1996; Vol. 9, pp. 2-42 and references therein. [2] (a) G. Schill, Cutenanes, Rotaxunes, and Knors;Academic Press; New York, 1971; (b) D. B. Amabilino, J. F. Stoddart, Chem. Rev. 1995, 95,2725-2628; (c) J.-P. Sauvage, Acc. Chem. Res. 1998,31,611-619. [ 3 ] Some recent papers on catenanes: (a) D. B. Amabilino, P. R. Ashton, V. Balzani, S. E. Boyd, A. Credi, J. Y. Lee, S. Menzer, J. F. Stoddart, M. Venturi, D. J. Williams, J. Am. Chem. SOC. 1998,120,4294-4307; (b) D. G. Hamilton, N. Feeder, L. Prodi, S. J. Teat, W. Clegg, J. K.

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Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

5 Template-Directed Ligation: Towards the Synthesis of Sequence Specific Polymers Yahaloma Gat, David G. Lynn

5.1 Introduction The structure of the DNA double helix first highlighted the simple elegance of the most sophisticated template reactions known, template directed polymerization. Through these reactions the genomic information is accurately replicated in DNA, transcribed into RNA, and translated into protein. Over 40 years ago, Crick combined these reactions into the “Central Dogma” of biology (Figure 5-l), a formulation suggesting that all living things follow this basic chemical plan [ 11. Today, even with the incredible biological diversity known to exist on Earth, no violations of this chemical scheme are known. The nucleic acids store the genetic blueprint, and the co-catalytic proteins function cooperatively with this molecular template to express the encoded information. Over the last four decades, synthetic non-enzymatic oligonucleotide ligations have been explored as potential models for the evolution of replicating systems on the early Earth [2-111. These studies have explored ligation reactions that occur on a template without protein/enzymatic catalysis. Such systems have both provided mechanisms for the early evolution of biopolymer catalysts and placed limits on template directed ligation. More recently, the lure of antisense molecules capable of disrupting specific gene expression has resulted in the exploration of backbone-modified nucleic acids [ 12-33].

\

n

RNA

W

DNA

*’~*%%>

\

Protein

Figure 5-1 The “Central Dogma” as formulated in 1958 with probable (solid arrows) and possible (broken arrows) reactions as indicated (adapted from [ lb]).

134

5 Template-Directed Ligation

At the same time, several laboratories have used in-vitro selection strategies to identify RNAs and DNAs that catalyze specific reactions [34-401. The information from these and related studies now opens the possibility of expanding the molecular skeletons capable of storing sequence information into ones that can be read into complementary materials [41]. Since it has not been possible to cover all the valuable contributions that have been made in these fields of study, we have instead organized the discussion around a minimal scheme for template directed ligation. This minimal scheme will be compared with the autonomous natural genomes that self-replicate via template directed polymerization reactions. The advantages and limitations of each step in the minimal scheme are discussed with respect to the structural diversity in the template that will make it possible to extend these reactions to new materials and new polymerization strategies.

5.2 Template-directed Ligation: Minimalist Scheme The overall catalytic efficiency of the template, as analyzed by Michaelis-Menten kinetics, is expressed as a function of both binding affinity and rate enhancement. K,, the substrate concentration necessary for half-maximal rate, can provide an inverse measure of binding affinity, and for native protein enzymes ranges from mM to PM. The catalyst rate enhancement is given by the turnover number, kcat, the number of substrate molecules transformed into product per unit time by a single catalytic site. Values of k,,, typically range from lo3to lo7 s-' for enzymes. The ratio of these two constants, k,,lK,, provides a direct measure of the catalytic efficiency at substrate concentrations that are significantly below template saturation. By considering the oligonucleotide templates as catalysts, a comparison with their enzyme counterparts is inevitable [42]. For example, the RNA component of RNAse P, which catalyzes the hydrolysis of tRNA, has a turnover number of only 1 min-', a K,,, of 0.5 PM,and a catalytic efficiency, kca,lK,, of 2 x lo6min-' M-' [43]. While RNAse P is a reasonable catalyst, its catalytic efficiency, like all known ribozymes, falls well below the diffusion-limited rates (> lo8 s-' M-') of an ideal catalyst where substrate turnover occurs with every substrate encounter [44]. The minimal scheme for a catalytic template directed ligation is outlined in Figure 5-2. In step 1, molecular recognition controls preorganization of the substrates along the template. The specificity, or fidelity, of the template directed synthesis is defined by the probability that the complementary substrate, rather than a non-complementary competitor, will be inserted opposite the appropriate site on the template. As can be seen in Figure 5-2, the difference in affinity between two substrates, S1 and SI', for the template, T, can be expressed as a difference in binding affinity, AAG = AGs - AGSIT.The energetics of this pairwise interaction between a substrate and the complementary strand define an effective molarity for the substrates. The association is entropically disfavored, not only due to the three degrees of translational and rotational entropy that are lost, but also because free internal bond rotations can be restricted by complexation [45, 461. Restraining either the substrate andor the template to resemble the bound conformation could reduce this entropic cost.

5.2 Template-directed Ligation: Minimalist Scheme

Figure 5-2 Scheme of template-directed ligation with steps 1,molecular recognition; 2, ligation; 3, product dissociation.

Substrates

Y

Y Y/

135

sy/

Template

SUbStrpts

, /

Template Product

-

The chemical transformation in the process, step 2, is the ligation. The reaction will be important to both catalytic efficiency and fidelity. kc,,lKm provides a direct measure of catalytic efficiency, and is also sometimes called the specificity constant [47]. On a single catalyst, the relative velocities of the reaction of two substrates S 1 and S 1’ at equal molar concentrations are proportional to the ratios of their respective kc,,lKm values. Thus, the discrimination between the two competing substrates is determined by this ratio rather than by either quantity alone. In principle, a ligation can exploit any reaction that would couple the substrate chain ends. However, the reaction will be constrained by the geometry required to bind the substrates to the template and little information is currently available to place limits on the selection of appropriate reactions. At least with the nucleic acids, the increasing knowledge and synthetic availability of modified backbones may allow the desired association energies and reaction geometries to be rationally engineered into the templates so that these parameters can be optimized. Clearly, product dissociation by this scheme, step 3, will limit turnover, as the product-template duplex will be stabilized over the substrate-template ternary complex. Maximizing AAG in step 1is required to enhance fidelity, but this increased affinity is generally present in the product duplex. Obviously if the binding affinity could be a tuned variable, high substrate affinity for ligation to maximize accuracy and reduced product affinity to enhance catalytic efficiency, product inhibition could be avoided. In Nature’s genomes, replication fidelity is primarily a kmetic function of the mechanistically complex DNA polymerases [43]. These enzymes employ activated phosphoric acid anhydrides leading to a final product-template duplex. The third step, dissociation of the product strand from the template, requires an additional input of chemical energy and a separate set of protein catalysts. Therefore each step in DNA replication requires a critical and complex set of translation products to ensure the production of a single copy of the template, and for autonomous growth, the template must be of sufficient size to encode all of the required catalysts for the process. The notion that these templates must encode catalysts, or possibly even the templates themselves serve as catalysts for more than one reaction, becomes an important feature for the development of template autonomy.

136

5 Temulate-Directed Lipation

5.3 Catalytic RNA and DNA Ribozymes [48-551, discovered in the early 1980s, documented the ability of RNA to fulfill both roles of information storage and catalysis. Prebiotically, in an “RNA-world” scenario which proposes that RNA molecules led to the appearance of early life [56,57], RNA replication is expected to follow the steps in Figure 5-2. However, known ribozymes catalyze a rather narrow range of reactions at phosphoryl centers [58-601. Invitro selection methods have broadened the catalytic repertoire to include also 2‘-deoxynucleic acids. Thus, the 2’-hydroxyl group, believed to be critical for the catalytic activity of ribozymes, is unessential in DNAs that cleave RNA [36, 371, promote self-cleavage [38], and catalyze ligation of chemically activated DNAs [35]. For example, E47 is a 47-mer DNA ligase shown to have an initial rate of ligation that is lo3 greater than the rate of catalysis given by a simple complementary template 13.51. The catalyst was however severely limited by product release, and even at saturating substrate concentrations, the turnover number was only 0.66 h-’. With selection methods, the catalytic activity of RNA molecules now includes reaction types as diverse as ester [61] and amide bond formation [34], bridged biphenyl isomerization [40], and porphyrin metallations [62a]. Selections for amide formation yielded RNAs that were able to catalyze the transfer of an amino acid to their own 5’hydroxyl group [34]. The selected sequences contained a 13-nucleotide invariant stretch that was hypothesized to serve as an internal template bringing together the aminoacyl group of the substrate and the 5’-hydroxyl of an RNA library. By making a derivative in which the 5’-hydroxyl was replaced with a 5’-amino group, the modified ribozyme was found to transfer the amino acid almost as efficiently as the initially selected ribozyme, but the overall rate enhancement was still low, with a k,, of 0.19 min-I. With porphyrin metallation, selected DNA and RNA catalysts were less efficient than the native ferrochelatase, but the catalytic efficiency of the ribozymes was comparable to that of an antibody selected for the same function [39,62a]. The size of the nucleic acid, however, was ca. - 8 kDa, whereas the protein was five times larger [62b]. In order to overcome the shortage of catalytically active functional groups in RNA, invitro selections have been combined with nucleobase modification [63, 641. Uridine derivatives modified at C-5 of the nucleobase were first shown to be substrates for RNA polymerase, and then were incorporated into selected RNAs. In one case, an incorporated imidazole-modified uridine was employed to catalyze amide bond formation and a rate enhancement of lo4- lo5 over the uncatalyzed reaction was observed [63]. RNA sequences using native UTP were completely inactive, establishing that the imidazolemodified uridine was crucial for catalysis. In a second study, uridine bases attached to pyridine were incorporated and found to accelerate the rate of a Diels- Alder cycloaddition [64]. The pyridine was hypothesized to form Lewis acid complexes with transition metals to catalyze the reaction. In contrast to most catalytic RNAs, in these two studies nucleobase templating was not required for catalytic activity. Clearly, like proteins, nucleic acid oligomers are able to catalyze reactions through a variety of mechanisms and their catalytic range can be extended with synthetic modifications.

5.4 Molecular Recopnition

137

5.4 Molecular Recognition The nucleic acids represent the most obvious and best-understood templates in the context of the minimal scheme shown in Figure 5-2. While hydrogen bonding and aromatic stacking of the bases define molecular recognition along the template strand, it is increasingly clear now that the backbone contributes significantly to duplex stability. In this section, the effects of backbone substitution are organized and discussed with respect to duplex stability. The discussion will go beyond Watson-Crick duplexes in order to generalize template directed ligation more broadly to other classes of molecules.

5.4.1 Sugar Substitution The existing ribose modifications (Figure 5-3) have generally altered backbone flexibility. For example, an open-chain glycerol backbone, effectively arising from the removal of the C-2’ ring carbon of the sugar, has considerably more degrees of freedom than the native backbone (Figure 5-3) and when hybridized with native DNA, the duplexes exhibit dramatically reduced melting temperatures (T,) [65]. The 9-mer 5’CTTTTTTTG-3’, with two glycerothymidine substitutions in the center of the strand, gave a T , of only 11 “C, compared to 40 “C in the native duplex. In contrast, the hexose-oligonucleotides [66-681 and bicyclo-and-tricyclo-DNAs [69-7 11 rigidify the backbone and have generally shown greater duplex thermal stability. The bicyclo-DNAs have the C-3’ and C-5’ carbon atoms of the ribose connected via an ethylene bridge, and the related tricyclo-DNAs have an additional annulated cyclopropane. The recently introduced locked-nucleic acids (LNAs), have an oxymethylene linker between C-2’ and C-4’. LNA obeys the Watson-Crick base pairing rules whereas the bicyclo-and-tricyclo-DNAs preferentially accept a complementary strand on the Hoogsteen face. Nevertheless, base mismatch formation is strongly destabilized in these structures, and the more rigid backbones can play a crucial role in duplex stability and base selectivity. In homo-DNA (h-DNA) and pyranosyl-RNA (p-RNA), the hexitol ring is frozen in a single 3’-endo-like conformation, as opposed to the multiple conformations accessible to the furanose of DNA and RNA. The h-DNA duplexes have a quasi-linear orientation as opposed to the superhelical structure of DNA duplexes, and the distance between the base stacking planes is larger relative to that of DNA. The h-DNA duplexes also have different pairing stability, e.g., the pairing priorities of A-A exceeds that of A-T. In contrast to h-DNA, p-RNA, which is also quasi-linear, does not show altered pairing priorities. The hexose rings in these analogues have a different regiochemistry of attachment to the backbone - C-6’, C-4’ in h-DNA and C-4’, C-2’ in p-RNA - and the base stacking is different. For example, studies of self-complementary sequences, such as 5’TTTTAAAA-3’ and S’-AAAATTTT-3’, which show equivalent energies with native duplexes, are quite different with the modified backbones. In p-RNA, the T, for the duplex of the first sequence is much higher than that of the second. In h-DNA, the situation is reversed and the duplex of the second sequence is more stable than the first. The different backbones have been proposed to alter the inclination between the backbone

138

5 Templute-Directed Ligation

Figure 5-3 Ribose-modifiednucleic acids. B designates a nucleobase.

axes and the axes of the Watson-Crick base pairs and to result in an opposite directional orientation of the stacked bases in the two duplexes [68]. It was concluded that an opposite orientation of the backbone inclination correlates with the differential stability in the resulting duplexes. These changes in the backbone sugar and the regiochemistry of attachment clearly have a dramatic effect not only on the association energies but also on the overall topology of the duplex.

5.4.2 Phosphate Substitution Modifications at the phosphorous center, including the phosphorothiolate, methylphosphonate, and phosphoramidate derivatives, have generally shown reduced binding affinity for their RNA targets [ 191. Replacement of the phosphate generally destabilizes bind-

5.4 Molecular Recognition

139

ing [ 19, 29,301, except in a few cases where the linkage restricts conformational flexibility within the complex [ 19-21, 3 1, 721. The repeating charges along the phosphate backbone appear to play a critical role in both strand pre-organization and strand-strand orientations in the duplexes, enforcing an extended conformation in both structures [72]. This conclusion was further explored by the structural analysis of a duplex with a single phosphate replaced with an alkylamine linkage, 1 (Figure 5-4).Solution NMR struc-

Figure 5-4 The basic structure of duplex 1 with the aminoethyl linkage in the TT central region as indicated with the box.

140

5 Template-DirectedLination

tures established that both 1 and the native all-phosphate duplexes exist in the canonical B-DNA conformation with Watson-Crick base-pairing preserved. The aminoethyl linkage in 1, in contrast to the native phosphodiester, permitted detailed NMR analysis of the backbone geometry. Within the minimized structure, Figure 5-5, the CH, that replaces the native PO; is flexible and free to collapse into a hydrophobic core formed by the base edges and sugar rings of the flanking TT/AA nucleosides of the duplex (a). This conformation is significantly different from the maximally solvent-exposed orientation of the native phosphate in DNA (b). The stippled rendering of the van der Waals surface highlights the charge distribution. Strand association energetics of the unmodified duplex were estimated by the nearestneighbor approximation [73] yielding calculated A H values consistent with those determined by both UV hyperchromism and 'H-NMR analyses [72]. The corresponding analyses of the modified duplex 1 showed both that it was destabilized relative to the native duplex and that the overall decrease in stability originated from two opposing factors, a large decrease in enthalpy and a compensating favorable change in entropy. Other structural analogues, prepared to remove the positive charge in the backbone, as well as data from the literature [18, 191 suggested that the positive charge was not the major factor contributing to duplex stability. The entropic difference between the native and the modified duplex 1 was attributed to the ability of the aminoethyl linkage to collapse into the hydrophobic core of 1.

Figure 5-5 Comparison of structures of the TT region of (a) duplex 1, and (b) native duplex in B-form DNA. Both strands were cut out of the full duplexes, generated (a) from molecular dynamics simulations incorporating NMR constraints, and (b) from crystal structure data [ 1231. The intruding C7' methylene with the flat solvent-accessiblesurface in the modified linkage 1 contrasts markedly with the maximally solvent-accessiblephosphate of the phosphodiester linkage. The solvent-accessiblesurfaces are stippled (adapted from [72]).

5.4 Molecular Recognition

141

A structural model incorporating these data was developed to explain how such a change in the local backbone conformation could disrupt the long-range cooperativity of DNA duplex formation [72]. As outlined in Figure 5-6, the hydrophobic methylene unit can partition from the usual solvent-exposed position of the PO; group (a) into the hydrophobic interior of the double helix (b). This movement accounts for the favorable AS, but accentuates the gap between the two flanking phosphates, forcing a movement to shorten their intervening distance. This change destabilizes the optimal topology for duplex stability (c). The overall decrease in the stability of duplex 1 results from a global decrease in base stacking and hydrogen-bonding interactions between the base pairs. The model in Figure 5-6 suggests that both backbone flexibility and heterogeneity contribute to duplex destabilization. Backbone heterogeneity was investigated in the amide-linked thymidine g-mer, (dTN)8.This strand was readily synthesized by solidphase synthesis (Figure 5-7) and forms a heteroduplex with the native adenine 8-mer, (dA),, a duplex whose stability and selectively is comparable with that of the all-phosphate duplex [74]. Titration experiments have suggested that these strands form a heteroduplex with a T, identical to the native duplex. However the heteroduplex stability has a strongly attenuated salt dependence and maintains the same T, in the absence of salt. While this backbone homogeneity along the strand is important, it is likely not to be the only factor that is responsible for the stability of the (dA)8-(dTN)8 duplex. The dimethylene sulfone RNA, rSNA [28], was studied as a symmetrical octamer and duplex formation was shown to be destabilized as a result of single-strand folding. Therefore, flexibility within the linker is also important, and phosphate charge repulsion and/or conformational rigidity are critical for pre-organizing an extended single strand. The optimal degree of flexibility in the backbone is also likely to be base sequence dependent as the

a

b

C

Figure 5-6 (a) Duplex 1 with the negatively charged phosphate removed initiates (b) collapse of the aminoethyl linkage into the hydrophobic interior of the duplex. The remaining phosphatcs minimize their separation along the strand, causing (c) backbone curvature and loss 0 1 the optimal geometry for base-stacking and H-bonding interactions.

142

5 Terndate-Directed Liaation

lo$

Solid-Phase

-.

... .

FMocl.N-/

\

Figure 5-7 Schematic diagram of solid-phase synthesis of amide-linked oligonucleotides.

base affects both the energy of association and the resulting topology within the single strand.

5.4.3

Neutral Acyclic Backbones

The peptide-nucleic acids (PNAs) [22-261, replace both the ribose ring and the phosphate of the backbone with an amide linkage (Figure 5-8). PNAs form strong duplexes and triple-helical structures with DNA, and the binding occurs with a specificity similar to that observed in the formation of the corresponding DNA-DNA structures [24]. The observation that a PNA strand could displace the corresponding DNA strand from a preexisting duplex highlights both the stability and dynamics of these structures [22]. The three-dimensional structure of a PNA-DNA-PNA triple helix was shown to differ notably from the all-DNA triplexes [25]. It appeared that the flexibility imparted by the replacement of sugar phosphate with the PNA backbone allowed for conformational changes that improved base stacking. However, recent molecular dynamic simulations have challenged PNA flexibility as the reason for triplex stability, and instead have suggested that a conformational preference of the PNA strand itself is responsible [26].

5.4 Molecular Recognition

51

i

5'

I43

< dN-" 5

0.

B

7 = O

H-NYB \ r("-" 0 =c

0

/C=O

DNA

3

3'

PNA

QPk4.A

H-NYB 3'

9lanvl-PNA

Figure 5-8 Structure of DNA, PNA, OPNA, and alanyl-PNA. In alanyl-PNA, the peptide strand is represented with the absolute chirality alternating at each residue along the strand. B designates a nucleobase in all structures.

Several laboratories have now prepared PNA analogues [27,75,76], and among these the oxy-PNA (OPNA) is noteworthy (Figure 5-8) [77]. The ether linkage in OPNA improves water solubility, and enhances sequence specificity in duplex association. The melting temperatures of DNA (thymidine 12-mer) with one equivalent of complementary DNA, OPNA, and PNA (adenine 12-mers) are 30 "C, 43 "C, and 55 "Crespectively. The OPNA-DNA duplex has an intermediate T, and shows a very sharp, cooperative melting transition. The DNA-PNA complex shows mixtures of duplexes and other structures, probably triplexes, which contribute to the high T,. Circular dichroism (CD) analysis detects no helical structure in the single strand of OPNA, consistently with the flexibility of the backbone. Thermodynamic parameters show that both the enthalpic change (AH) and the conformational constraints (AS) are largest in the OPNA-DNA complex, suggesting that upon hybridization with native DNA, the randomly coiled OPNA is folded into a regular duplex with optimized stabilization energy. The OPNA strand appears to conform better to the constraints of the more pre-organized DNA complementary strand in duplex formation. Flexibility within the backbone allows complementary associations to take many forms. Such topological diversity is apparent in the alanyl- and phomoalanyl-PNA variants [78-821. Alanyl-PNA (Figure 5-8) contains an a-amino acid backbone c a w ing the nucleobases as side chains. They differ from the original PNA in two major respects. First, the amide linkage between the nucleobase and the backbone is replaced with a methylene, giving increased conformational flexibility to the base. Secondly, the backbone linkage is shortened, and higher densities of nucleobases exist along the chain.

144

5 Template-Directed Ligation

This combination of both greater nucleobase flexibility and increased base density contributes to alter pairing and geometric arrangements in the duplexes. For example, A-A pairing in alanyl-PNA is more stable than A-T, a structural feature seen in linear stretches of DNA and RNA [83, 841, in h-DNA [66], and in Phomoalanyl PNAs [80-821, which differ from alanyl-PNA by an additional methylene in the backbone. The Phomoalanyl PNAs can exist in higher-ordered structures with linear backbones which self-associate through hydrogen bonding into Psheet conformations. That these higherordered aggregates are driven by strong adenine self-pairing is supported by structures modified with 7-carbaadenine nucleobases. The adenine hexamer has T, > 90 "C and more than 70% hyperchromicity, which drops to T, = 35 "C with 24% hyperchromicity in the 7-carbaadenine hexamer. Therefore, in the Phomoalanyl PNAs, the nucleobases can be stabilized by hydrogen bonding through both Watson-Crick and Hoogsteen faces. Clearly, as the backbones become increasingly flexible, the nucleobases can dictate self-association in an increasingly diverse range of topologies.

5.4.4 Peptide-Peptide Association Certain peptide backbones also self-associate, and in some, the association energies can be very large. Collagen fibrils, tropomyosin and actin filaments, viral and other cellular inclusion bodies, hemoglobin S tactoids, prions, and amyloids all represent highly ordered supramolecular aggregates. Like DNA duplexes, these paracrystalline materials attain long-range order, but not in all three dimensions. One of the smallest of the peptides that form amyloids are the AP peptides associated with Alzheimer's disease [ G I . These proteolytic fragments of the amyloid precursor protein form large fibrillar paracrystalline aggregates (Figure 5-9A). The AP peptide fibers are known to be dominated by P-strand conformations, but further efforts to understand their structures have been limited by the inherent insolubility of the material. Synthetic attachment of a polyethylene block at the hydrophobic C-terminal of a truncated AP peptide, residues 10-35,2,generated a soluble fibrillous material whose aggregation is controlled by simple changes in concentration, pH, or ionic strength [86]. The increased solubility of 2 appears to be mediated by prevention of fiber-fiber association (Figure 5-9B). PStrand peptides are notoriously insoluble and the strategy employed in the construction of this block copolymer represents a significant opportunity to investigate the thermodynamics of self-association and the exploitation of these materials as templates. NH,-~EVHHQKLWFAEDVGSNKGAIIGLM- Nqo-fxo-0H

2

Dipolar recoupling solid-state NMR experiments established that the central core region of the peptide AP (10-35) was both ordered and homogeneous [87]. The entire length of the peptide has now been shown to exist in an extended pconformation with each pep-

5.4 Molecular Recoanition

145

Figure 5-9 Electron micrographs of (A) AP (10-35), and (B) AD (10-35)-PEG fibers (adapted from [86]).

tide arranged parallel to the others and with each amino acid residue in register from peptide to peptide along an extended psheet [88]. Similar analyses have now been applied to the protein block of 2. The peptide domain of the block copolymer is arrayed in the center of the fibril [89] and retains the same parallel, in-register pstructure of AP (10-35) [90]. The PEG block is therefore localized to the surface of the fibril, reducing fibril-fibril contact sufficiently to maintain solubility. Preliminary experiments have suggested that the phelical sheets exist in laminated blocks, again in a parallel, in-register orientation, and held together by side chain-side chain interactions (Figure 5-10) [90]. This unique arrangement is consistent with the fiber dimensions determined by electron microscopy and neutron scattering experiments. The Psheet secondary structure is energetically dependent not only on the hydrogen bonding interactions between individual strands, but also on the ability of the resulting sheet to twist, bulge, and fold into multifaceted conformations [91-941. Consequently, amino acid propensities have proven to be highly dependent on context, greatly complicating the design of pstructure peptides and proteins [95,96]. Most problematic however are the intermolecular interactions which compromise solubility, the infamous feature of the many amyloid diseases [85,97]. In the block co-polymer 2, the energetics of selfassociation of amyloid peptides dominate the paracrystalline &sheet structure in the core of the fibril array while the C-terminal polyethylene glycol, localized on the surface of the fibril, ensures solubility. The surface-localized PEG, much like the polar phosphates of the nucleic acid polymers, enforces an overall amphiphilic character of the fiber strand.

146

5 Template-Directed Ligation

B.

A.

t

Figure 5-10 (A) The fiber is composed of peptides arrayed in a parallel Psheet with residues in register. (B) Up to six Psheets can be laminated together to define the fiber thickness with the peptides oriented perpendicular to the direction of growth of the fiber. Side chain-side chain interactions stabilize the lamination.

The interior of the DNA duplex is organized by hydrogen bonding and aromatic base stacking interactions while the charged backbone ensures a micellar-like orientation to the overall structure. In contrast, inter-strand hydrogen bonding stabilizes the extended backbone pconformation while side chain interactions, hydrophobic side chain interdigitation, aromatic stacking, and salt bridge formation contribute to tertiary structural sheet and lamination stability (Figure 5- 10).The orientation of these interactions are different, with both the peptide backbone and side chains contributing to inter-strand stability, but the end result is remarkably similar. The individual amino acids stack in register along the sheet, suggesting a template capable of dictating sequence-specific ligation. The extent to which these structures can serve in template directed ligation will depend on many factors that have still to be established.

5.5

Ligation

The elegant simplicity of the DNA double helix [98] has provided inspiration to bioorganic chemistry since its discovery in 1953. DNA templates for ligation reactions were suggested [99, 1001, but not experimentally explored until 1966 [2]. Deoxyadenosine oligomers were shown to template the ligation of short thymidine oligomers (5- and 6mers) with carbodiimide activation to the 10- and 1Zmer products in 3% and 5% yields, respectively [2]. The first demonstration that a template of defined sequence could catalyze the formation of its complementary strand was shown by Orgel et al. using nucle-

5.5 Lipation

147

oside 5’-phosphoimidazolides as activated monomers [3 -51. Under non-enzymatic conditions, dCCGCC templated the synthesis of dGGCGG in 18% yield from a mixture of activated guanosine and cytidine monomers [5]. This oligomerization was shown to be enantioselective by demonstrating that the Lenantiomer terminated the oligomerization of the D-enantiomer. Under these conditions, h-DNA, containing the six-membered hexitol ring frozen in a single 3’-endo-like conformation, was more enantioselective than DNA or RNA templates [101, 1021. Since duplex structure does correlate with sugar pucker, 2‘-endo for B-DNA and 3‘-endo for A-DNA [ 1031, the effectiveness of the ligation on the hexitol template has led to the suggestion that an A-DNA structure provides a better template. This suggestion is also supported by the observation that addition of Co3+ ions, known to induce a B-DNA to A-DNA transition [ 1041, improves the ligation effectiveness. von Kiedrowski achieved the first successful molecular replication with the self-complementary hexamer dGGCGCC [7]. This template catalyzed the ligation of two complementary trimer substrates using carbodiimide as the dehydrating reagent. The system allowed for each newly assembled strand to be identical to the template, demonstrating autocatalysis, but the hexamer did not allow for exponential amplification. The combined yield after four days was less than 12%, and product duplex dissociation was limiting. In 1994, the system was expanded to include four templates, two complementary and two self-complementary, which through cross-catalytic self-replication, compete for the common trimeric precursors [8]. The replication efficiency was similar with both complementary and self-complementary templates. In an attempt to exploit the thermodynamics of template association, an imine, formed by reversible condensation (Figure 5- 1l), was synthetically incorporated in the DNA

HO-dCG--d

HO-dCG -0

H.

0 H

HO-dCG--d

[Template: HO-dGCAACG-OH]

Figure 5-11 The reversible imine-coupling reaction. The modifications were designed to maintain equivalent numbers of atoms in the linking domain.

148

5 Template-Directed Ligation

backbone [ 105, 1061. The equilibrium constants in Figure 5-12, K , - 4 , were determined directly from ‘H- and “N-NMR experiments [ 1071. The relative concentration of the duplex to the free imine single strand, expressed as a function of K 2 / K 4 ,was 10’ or higher. Under reducing conditions, the rates of reduction were dominated by this large difference in concentration, and significant fidelity was achieved when the complementary amine was allowed to compete with non-complementary substrates [ 1051. The model shown in Figure 5-6 argued that linker flexibility was critically destabilizing and that the more rigid imine, containing two sp2 centers and significantly fewer degrees of conformational freedom, should form a more stable duplex [72].

Thermodynamic Cycle (SlX10-4) + H I 5 N 4

K3

(23.3~10~)

Figure 5-12 The thermodynamic cycle for DNA-directed imine formation and the measured equilibrium constants for each step (adapted from

[1071).

This approach of using a reversible initial ligation was extended in the coiled-coil peptide templates [108-1121. The amide synthesis strategy, shown in Figure 5-13 [ I 131, is sufficiently chemoselective to allow utilization of peptide fragments without side chain protection. A thioester at a peptide C-terminus appears to undergo rapid exchange of thi01 that is trapped by a spontaneous intramolecular condensation with the amine of the Nterminal cysteine. The generated thioester is not observed as a discrete intermediate because of the rapid S,N-acyl rearrangement through a five-membered-ring transition state to give the peptide bond. By this strategy, a-helical segments based on the leucine-zipper motif catalyzed template directed ligation of the complementary peptides. The rearrangement step was relatively slow, t,,* > 1 min, probably retarded by conformational requirements of the reaction occurring on the template [ 1091. Nevertheless, the ligation gave rate enhancements of lo3 over the uncatalyzed reaction. The parabolic growth observed under replicating conditions was attributed to product inhibition [ 1091. Other catalysts, sensitive to environmental conditions [ 110- 1121, were designed by placing ionic residues at the e and g positions of the helical heptad repeats of the coiled coil. With glutamic acids at these positions, the duplex is stable under acidic conditions. Under physiological conditions, the side chain acids are negatively charged and the coiled coil is destabilized. With lysine residues at these positions, either basic conditions,

5.6 Product Dissociation 0

0 II

II

-C-SR

I49

Figure 5-13 A thioester at the C-terminus of one peptide serves as the electrophile for bimolecular condensation with the thiol side chain of an N-terminal cysteine residue. The S,N-acyl intramolecular rearrangement forms the native amide bond.

SH

or neutral conditions with high salt, allowed for template directed ligation [1111. A fourfragment auto- and cross-catalytic peptide system under these conditions enhanced replication efficiency [ 1121, but the rate constants derived from this system once again highlighted the inherent contradiction plaguing template directed ligation: a stable template-substrate complex suffers product inhibition, while a weak template-substrate complex reduces catalytic rate.

5.6

Product Dissociation

Protocols based on cycling the temperature or other environmental parameters capable of melting the product-template duplex after each cycle shown in Figure 5-2, provide a general approach to avoid product inhibition [3, 105, 1061. Encoded enzymes provide this function in natural genomes and physically melting the duplex product at the end of each cycle controls the polymerase chain reaction [114]. In both cases, exponential growth of the template is possible. However, several synthetic variations have also been suggested to overcome product inhibition. Luther et al. have circumvented product inhibition by attaching the template to the surface of a solid support [115]. Two complementary DNA 14-mers, immobilized irreversibly on the support, templated the ligation of four 7-rner DNA substrates. After the cow pling step, the product strands were released by denaturation, and subsequently immobilized on fresh support to become a template for the next reaction cycle. This procedure requires several steps, but allows exponential amplification of oligonucleotide templates. In a separate approach, the nucleotide template was expanded to a double-helical structure [ 1161. The Hoogsteen pairing in the triple helix is relatively weak, thus facili-

150

5 Template-Directed Ligation

tating release of the newly generated strand from the double-helical template. An increase in pH or the iddition of excess substrate destabilizes the product complex. The approach requires symmetrical sequences in order to regenerate the template and one of the strands must be all purine for triplex formation. Still, three successive replication cycles were demonstrated giving roughly a five-fold increase in the total amount of the initial 24-mer duplex. Hoogsteen pairing was further employed as a triplex-directing template with a circular DNA [ I 171. This pyrimidine-rich circular template (44-mer) gave improved thermodynamics of substrate binding (6-mer + 1 1 -mer homopurine); quantitative ligation vs. 5 1% yield using linear DNA, and a 23-fold rate increase. Thus, this single-turnover ligation on the circular template through triplex formation was shown to be more efficient compared to the linear template. It may be possible with further structural modifications to extend this system to multiple turnovers. As suggested above, modifications in the linker domain have a dramatic effect on duplex stability and have suggested other strategies to avoid product inhibition. The addition of a reduction step in the imine cycle is shown in Figure 5-14. While the fidelity of the process will be limited by the ratio of the equilibrium constants, K 2 / K 4 ,product inhibition is controlled by the relative duplex stability of the amine product relative to the imine substrate. Based on the model in Figure 5-6, the amine product could be predicted to be less stable than the imine, and indeed, the product duplex 1 was found to be significantly less stable (> 106-fold), hence product inhibition was avoided. With 0.01 molar equivalents of DNA, the turnover number was 13 min-' and there was no effect of

Catalytic Cycle

(1.2x 102)

[Produet)

Figure 5-14 Full cycle for the DNA-catalyzed reductive ligation of amine and aldehyde fragment (adapted from [ 1071).

5.6 Product Dissociation

151

product concentration, at least through the first half-life where the product/template ratio exceeds 50 : 1. Therefore, the rigidity and resulting stability of the imine duplex, together with the flexibility and instability of the product amine duplex, allow this small nucleic acid template to function as an efficient catalyst [107, 411. The reaction itself, however, is more similar to a biological translation reaction, converting a phosphate backbone into an amine backbone. The question posed in Figure 515 is whether this translation product, which can be prepared with significant amplification, could be used to aid in the replication of the original template. This strategy is different from the natural system in that the translated product serves as the template catalyst for construction of its phospho-linked parent. The aminoethyl linkage is more flexible than that of the phosphate [72], and therefore should less effectively pre-organize the substrates than does DNA. However, catalysis of phosphodiester formation with this template was comparable with that of a DNA template and this effect was attributed to the hydrophobic character of the alkylamine [72]. This assertion was supported by substitution of the nitrogen with alkyl groups, a modification that significantly increased both the hydrophobic character and the catalytic efficiency of the template [ 1181. Overall, the first step in Figure 5-15 can give greater than 106-fold amplification and the product can provide an effective ligation catalyst to reconstruct its parent DNA template. If viewed as a single replication cycle, products far in excess of the exponential growth seen in a single turn of the biological cell cycle are obtained. Extensions of this design for replication systems that achieve greater than exponential growth should be possible. Another hypothetical extension has emerged in the amyloid area. The simplified scheme shown in Figure 5-2 predicts that any material capable of increasing the effective molarity of properly oriented molecules along its surface could catalyze template directed ligation. While the association energy for fibrillogenesis has not been quantified, it must be large to generate the peptide arrays that exist in the fibers. Both the backbone

I' = I

"m,,,,,p

OBPO

Figure 5-15 Two-stage replication. The initial phospho-linked template is translated into amine product with amplification. The translated product-template catalyzes the synthesis of the original phospho-linked strand.

I52

5 Template-Directed Ligation

and the side chains participate in strand-strand association, and, the residues in AD (10-33, are aligned in register along the entire length of the peptide. The PEG block copolymer solves the most critical limitation of sheet structures, that of solubility. Therefore, the minimal scheme shown in Figure 5-2 can be modified to that shown in Figure 5-16.

+ -

S1

L s2

Molecular

Figure 5-16 Template directed synthesis on a p sheet template. The dyad template, consisting of n strands, organizes the fragments S 1 and S2 through molecular recognition. Each ligation cycle produces a new p sheet template, consisting of n+2 strands.

The product dissociation step is removed from the cycle entirely and the products are recovered after many cycles by disrupting the large soluble fibril arrays. The template is predicted to organize fragments S1 and S2 on both sides of the template such that each turn of the cycle would generate two new strands. For a proposed higher-ordered laminated structures, this stoichiometry should be scale as the number of laminae. The extent to which this strategy can be exploited is unknown and will depend on the mechanism of association of the peptides, the fidelity of the ligation, and the solubility of the fibril. There is clearly now sufficient synthetic flexibility to allow these variables to be optimized and exploited for template directed ligation or polymerization.

5.7

Summary

Intermolecular associations capable of templating specific reactions are central to both biological catalysts and to present-day catalyst design. The nucleic acid polymers have high association energies, well defined topologies, and encode information at an extremely high density. It is equally clear that they are able to catalyze a wide range of chemical reactions. However, oligonucleotide catalysts that use base pairing for molecular recognition are destined to be turnover-limited in the replication cycle of Figure 5-2. Turnover rates are increased by introducing mismatches and shortening recognition sequences [ 1193, or by insertion of mutations that weaken tertiary interactions [ 1201, but such changes lower fidelity and necessitate catalysts of higher molecular weight. Evolutionarily, in an RNA world scenario where no proteins exist, an autonomous RNA template could encode ribozymes as co-catalysts to provide the origin of self-rep-

References

153

licating entities. Product saturation limits the known ribozyme catalysts I121 - 1221, and ribozymes capable of melting duplex structures are certainly required for efticient replication. In addition, oligonucleotide biopol ymers appear less adept than proteins in organizing functional groups within active sites for catalysis. This limitation results first from the scarcity of catalytic functional groups in these polymers but, more critically, is a consequence of the phosphate backbone. While this backbone has greater degrees of freedom than the protein backbone, the necessity to shield the anionic phosphate groups enforces an extended conformation and prevents close packing within the structure. This stabilization is readily achieved in the tertiary and quaternary folds of proteins, for example, by creating local environments of low effective dielectric 1421. The solvation equirements in oligonucleotides limit folding into tertiary and quaternary structures that can function cooperatively during catalysis [42]. On the other hand, in a minimal catalytic model system, the ribozymes have advantages over protein enzymes. Even short oligonucleotides can effectively use duplex formation to bind substrates and the known ribozymes are generally smaller than their protein counterparts. This substrate recognition through secondary structure is not a common feature of protein binding sites, where tertiary structural folds are necessary to optimize close packing of residues distant in primary sequence [42]. As least conceptually, nucleic acid backbone modifications replacing the phosphate have the potential of both extending the functional groups needed for catalysis and allowing for more densely packed structures with well defined binding pockets. Such hybrid molecules can store information, serve as catalysts for template directed ligation, and be selected for catalytic function. Nature may have evolved the division of labor between the different classes of biopolymers as the genomes became larger and more specialized, but the opportunity for synthetic chemists to develop new materials capable of encoding information that can be translated, replicated, and selected for function is rich indeed. From the information now available, it should be possible to construct new autonomous genomes based on entirely different structural skeletons. We are currently limited only by our structural imagination and synthetic capability.

Acknowledgments We thank Jay Goodwin, John C. Leitzel, Peizhi Luo, Zheng-Yun J. Zhan, Timothy Burkoth, Tammie Benzinger, David Gregory, Jingdong Ye, and David Morgan for the insightful and creative experiments that made all of this possible and the NIH (Biotechnology Training Grant GM-08369 and R21 RR12723) for support.

References [ l ] ( a ) F. H. C. Crick, Symp. Soc. Exp. Biol. XI1 1958, pp. 138- 163. (b) D. Thieffry, S. Sarkar, TIBS 1998,23,312-316. [2] R. Naylor, P. T. Gilham, Biochemistry 1966,5,2722-2728.

I54

5 Templute-Directed Ligation

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157

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

6 Biomimetic Reactions Directed by Templates and Removable Tethers Ronald Breslow

6.1 Introduction Enzymes are remarkable both for their catalytic effectiveness and for their selectivities. Rate accelerations of 10000000000 or more are not unusual, and most enzymes show selectivity toward the substrates they act on, and toward the specific products they form from those substrates. The challenges in the construction of artificial enzymes are to achieve those rate accelerations and those specificities. In some respects achieving the product specificitiesis the most important goal. Substrate specificity is critical in the soup of components found in a biological cell, but chemical reactions can usually be performed on pure substrates where substrate specificity of a catalyst is irrelevant. However, the ability of an enzyme to achieve selective reactions on a particular section of the substrate (regioselectivity) and with specific stereochemical consequences (stereoselectivity) are features to be admired and imitated in chemical systems. Selectivity in simple chemical reactions is normally a reflection of the intrinsic reactivity of the substrate. For example, an oxidation would be performed by a relatively unselective reagent attacking the most easily oxidized part of the substrate. If that is not the desired position, it might be temporarily blocked, or the desired position might be activated in some way. This is not what enzymes do. Selectivity in enzymatic reactions is normally achieved by imposing the geometric control of an enzyme-substrate complex in which the catalytic group of the enzyme is held near the substrate so as to direct reaction to a specific spot, whether that spot is particularly reactive or not. For example, in the biosynthesis of cholesterol three methyl groups attached to saturated carbons in lanosterol are oxidized and removed even though there are much more reactive double bonds and a hydroxyl group in the molecule. This occurs because the substrate is held next to metalloporphyrin catalytic groups of the enzymes so that only the otherwise unreactive methyl groups are within reach. Many years ago, we set out to develop such methodology for synthetic chemistry, imposing strong geometric control on reactions that would otherwise show little selectivity, or would show undesired selectivity. We called this approach “biomimetic”, nonenzymatic chemistry designed to mimic the biological chemistry performed by enzymes [I]. In some cases, we imposed the desired geometric control by use of a direct tether between the reagent and the substrate, in other cases we used molecular complexing as a closer analogue to the enzyme- substrate complexing that determines biochemical selectivity. In this account of the field, we will describe both approaches. Although space lim-

160

6 Biomimetic Reactions Directed by Templates and Removuble Tethers

itations prevent a full account of related work from other laboratories, such related work is described more fully in some of the reviews we have written previously [l-301, particularly in references [4, 10, 15, 16, 19,24,26, 301.

6.2 Biomimetic Reactions Using Covalently Linked Tethers and Templates

6.2.1

Photochemical Functionalizations by Tethered Benzophenones

The first example in which a temporarily tethered reagent was directed to attack unactivated C-H bonds remote from the tether point was a study of the products from photolysis of esters of benzophenone-4-carboxylic acid 1 carrying long-chain alkyl groups (Scheme 6-1) [31]. The n-tetradecyl ester was attacked over carbons 8- 13, with half the

CH

w

\

C

/

J

Scheme 6-1 Photochemical remote functionalization of long-chain alkyl esters with a tethered benzophenone.

6.2 Biomimetic Reactions Using Covalently Linked Tethers and Templates

161

product from insertion of the benzophenone carbonyl into carbon 12. Products were determined by dehydration of the resulting carbinols and oxidation to produce carbonyl groups at the reaction point, and hydrolysis removed the benzophenone reagent and its tether from the functionalized alkanol. With longer chains, up to 20 carbons, the products indicated attack over greater distances, but again with significant insertion at C-12. The flexibility of the alkyl chains prevented the reactions from being fully selective, but the product distribution furnished information about the conformations of the flexible chains. This was examined further in subsequent studies, to be described. Steroids are rigid substrates without this flexibility problem, and whose selective functionalization is of considerable practical interest. Thus benzophenone-4-propionic acid was attached to 3cx-cholestanol and the ester 2 was photolyzed (Scheme 6-2) [32]. The only methylene group attacked was that at carbon 12 of the steroid, so ester cleavage, dehydration, and olefin oxidation afforded 12-keto-3a-cholestanol 3 as the only ketonic product. However, carbonyl insertion had also occurred at the methine C-H of carbon 14 of the steroid, revealed by lead tetraacetate cleavage and hydrolysis to form A'4-3a-cholestenol 4 and A8'14'-3a-cholestano15 . Some of the A14-3a-cholestenol4 was also formed on simple hydrolysis of the tethered reagent, as the result of direct dehydrogenation of the steroid by benzophenone excited-state triplet. Such direct dehydrogenation was later achieved completely selectively with a tethered benzophenone having different geometry, as described below.

4

2

5

Scheme 6-2 Photochemical remote functionalizationof 3a-cholestanol using a tethered benzophenone.

162

6 Biomimetic Reactions Directed by Templates and Removable Tethers

The introduction of a 9( 11) double bond into steroids is of practical interest, since such olefins can be converted to the 9-flUOrO- I I -hydroxy grouping found in most useful corticosteroids. Ester 6 had a benzophenone-4-hexanoic acid tethered to the hydroxyl group of androstan- 170-01 that curled under the steroid ring and photochemically inserted into the C-9 a-hydrogen, forming product 7 with a 9( 1I ) double bond after lead tetraacetate cleavage of the carbinol product and hydrolytic cleavage of the tether (Scheme 6-3) [33]. A product with a 14,lS double bond was also produced.

7

4

8 Scheme 6-3 Introduction of double bonds into steroids by remote functionalization.

In a full paper describing this and other functionalizations of steroids tethered to benzophenones [34], it was revealed that the 3a-cholestanol ester 8 of benzophenone-4acetic acid afforded, after hydrolytic removal of the tether, A'4-3a-cholestenol 4 as the product along with the diphenylcarbinol from reduction of the benzophenone. The short tether did not permit insertion into the C-14-H bond, so after the oxygen atom of excit-

6.2 Biomimetic Reuctions Usinp Covalentlv Linked Tethers and Templates

163

ed benzophenone removed the C- 14 hydrogen, the resulting steroid radical inverted to bring the C- 15 hydrogen within reach of the benzhydryl radical; it was selectively removed to afford the observed products. In a subsequent study [35], a deuterium was specifically placed in the 15a-position of the steroid, and it was demonstrated that this was indeed the atom that becomes attached to the carbonyl carbon of the benzophenone reagent. It was also found that a small amount of insertion of the benzophenone occurred into C-H bonds at C-12 and C-7 in addition to the previously reported 14-15 dehydrogenation. The products found in these studies indicated attack on the steroid at a predictable distance from the attachment point, except with highly flexible tethers, but the tether still permitted attack along an arc pivoting around the attachment point. This is a problem that was addressed in later work, to be described.

6.2.2 Free-radical Halogenations by Tethered Reagents In the course of carrying out the benzophenone photochemistry described in the previous section, we noted that the use of CC1, as solvent led to the formation of some chlorinated steroid products. Therefore we examined such halogenations further [36], and found that the simple free-radical chlorination of cholestanyl acetate with phenyliodine dichloride afforded the 9-chloro- and 14-chlorosteroids as the major products. Similar results were seen in bromination by bromotrichloromethane. We extended such selective radical halogenations to suppress reactions other than at C-9 and C-14 by appropriate substituent effects, but more significantly we used tethers to achieve essentially complete selectivity in the halogenations [36]. Attachment of phenyliodine dichloride with a rn-carboxy group as an ester 9 of 3acholestanol led to selective intramolecular chlorination at C-9 (Scheme 6-4). Hydrolysis of the ester led to HCl elimination, affording the A9(”)-cholestenol 10 as the main product, along with a little of the 14-15 olefin from intermolecular reaction. By contrast, attaching p-iodophenylacetic acid to 3a-cholestanol, then converting it to the dichloride 11, led to intramolecular chlorination at C- 14,with a small amount of more random intermolecular halogenation as well. This demonstrated that free-radical chlorination could be directed geometrically by the use of appropriate tethers. Furthermore, the chemical preference of the intermediate Ar- I-C1 radical for hydrogen abstraction from tertiary positions meant that the position of preferred attack was completely determined by the tether length, and unaffected by the ability of the reagent to swing in an arc about its attachment point. That is because the tertiary carbons with hydrogens on the a-face are all at quite different distances from C-3. In this work a reagent, an aryl iodide dichloride, was directly attached to the substrate through a tether, but it had disadvantages. With such a scheme only stoichiometric amounts of the reagent could be used, and the reactions led to some recovered starting material. Thus we considered whether a new process was possible in which we would use both a tether and a template to direct halogenations. We decided to try to invent what we called a “radical relay” process.

I64

6 Binmimetic Reuctions Directed by Templates and Removable Tethers

10 9

11

Scheme 6-4 Examples of free-radical halogenations of steroids by tethered reagents.

6.2.3 Free-radical Reactions Directed by Tethered Templates the Radical Relay Mechanism In the above halogenations, an iodophenyl group was attached to the steroid substrate, and then converted to the aryl iododichloride with C1, before the free-radical chain process was performed. We wondered whether we could generate the intermediate Ar- I-Cl radical that removes the substrate hydrogen by transferring a chlorine atom to the attached aryl iodide from an external reagent. That is, we wondered whether we could relay a chlorine atom from an external reagent to the iodine atom on the attached aryl iodide and thence to the hydrogen atom within reach. Such a process would be the analogue of throwing a baseball to the catcher who then reached down with it to tag the runner, or of kicking a soccer ball to a player near the goal who then propelled it into the goal itself. The chlorine atom radical relay was similarly successful. We irradiated a solution of phenyliodine dichloride with the rn-iodobenzoate ester 12 of 3a-cholestanol and found that C-9 chlorination occurred selectively, while no such selectivity was seen without the iodine atom on the benzoate ester [37]. Various controls established that we were not simply converting the attached iodoaryl template to its

6.2 Biomimetic Reactions Using Covalently Linked Tethers and Templates

165

dichloride, but were instead performing the desired radical relay process. That is, the free phenyliodine dichloride in solution was converted on photolysis to the Ph-I-CI radical, and this then transferred its chlorine atom to the template iodobenzoate group to form an attached Ar-I-C1 radical, as shown (Scheme 6-5). As expected from this, when the tethered template was the p-iodophenyl acetate, the process afforded the 1Cchloro steroid product. Similar results were obtained when the solution chlorinating agent was SO2CI,, and the solution radical was -S02C12.

I

I-Cl

+ Ph-I

O"0-I

12

\*\/\/

OZ I

+ Ph-iC1

Scheme 6-5 The radical relay mechanism.

Since this study led to a number of extensions, it is desirable to explain why the process works, and what its advantages are. The rate advantage of a radical relay process is that the hydrogen abstraction is intramolecular, rather than the intermolecular abstraction that would occur without the relay by the template. However, this explains it only in part, since the relaying of a chlorine atom from the radical in solution to the iodine of the template is of course an intermolecular process. Why is the two-step sequence - intermolecular chlorine atom transfer, then intramolecular hydrogen abstraction - faster than an intermolecular hydrogen abstraction by the free radical in solution? The answer is relat-

I66

6 Biomimetic Reactions Directed bv Temulates and Removable Tethers

ed to the reason why many enzymes carry out two-step sequences in hydrolysis reactions. That is, the serine proteases first attack an amide bond with a serine hydroxyl of the enzyme, then bring in a water molecule to hydrolyze the resulting serine ester. Why not simply use the water molecule directly to attack the amide bond? The advantage of the two-step process with serine proteases has to do with translational entropy [38]. In the first step, attack of an enzyme serine hydroxyl on the amide, the peptide is converted to an ester and the amine is released from the enzyme and recovers some of the translational entropy the substrate lost on binding to the enzyme. Then a water molecule is bound, losing entropy, but that is after the rate-determining step so it is irrelevant. If the second step were rate-determining, as it is when serine proteases hydrolyze esters instead of amides, the entropy lost by the water molecule would still have been compensated by the previous entropy gain from the released leaving-group fragment. In the radical relay chlorination of steroids, related arguments apply. Chlorine atom transfer to the large reactive iodine atom of the template from a radical in solution is relatively fast and easy, probably not rate-determining, and after the transfer the PhI is freely moving. The otherwise difficult attack at a hydrogen atom in the substrate is fast because it is intramolecular and template directed. The steroid radical then removes a chlorine from the solution reagent, regenerating the solution radical, but this is a fast intermolecular step that is not rate-determining. The result is that the template directed process dominates any random attack by solution radicals, and the reaction is thus positionally selective. The practical advantages of the radical relay process over the use of a tethered aryliodine dichloride reagent are several. First of all, an excess of the solution chlorinating agent can be used, so complete conversion of the substrate to product is achieved. Secondly, there is no need to premake an attached aryl dichloride by using Cl,, so sensitive substrates can be used. Finally, other templates can be used that can capture and relay a chlorine atom but cannot themselves be converted to dichloride reagents. These will be described later. It is important to note that in all of the chlorinations described above a chlorine atom is selective for the removal of a tertiary hydrogen atom, so the templates tethered on the a-face of the steroids can be positionally selective. That is, the tertiary hydrogens at C5, C-9, C-14, C-17, and in the side chain are all at different distances from C-3, where the tether is attached. Thus with a tether of defined length the intramolecular hydrogen attacks are quite selective. However, it is possible to design non-selectivity into the tethers. Models indicated that a rn-iodophenyl acetate tether should be able to direct chlorination to both C-9 and C-14, and this was found experimentally [37]. Both with the premade tethered aryliodine dichloride and with the radical relay process, an essentially equal mixture of C-9 and C-14 halogenation occurred. This is of course not a useful result, but it does indicate the extent to which molecular modeling can be used to predict the products in these reactions. We examined this further with molecular mechanics computer calculations [39]. The calculations accounted well for our experimental findings, including some we have not yet described here. However, the high selectivities we observed could only be accounted

6.2 Biomimetic Reactions Using Covalently Linked Tethers and Templates

167

for if we required that the collision of a chlorine atom bound to the iodine of a template had to occur essentially in line with the C-H bond being broken. This is not a general requirement of molecular mechanics calculations, and we suggested that it may reflect a requirement of the dynamics of the process. That is, we argued that collisions are effective only if their energy can be converted into vibrations of the substrate along the reaction direction, and that a more or less linear collision is required for effective energy transfer. We used our radical relay functionalization of C-9 in steroids to perform a synthesis of cortisone 13 (Scheme 6-6) [40]. The A9(") double bond in the steroid was hydroborated to allow an oxygen functionality to be placed at C-11, characteristic of corticosteroids. In more practical applications, the double bond can be epoxidized and opened to afford oxygen at C-11 and fluorine at C-9, as in many of the newer corticosteroid pharmaceuticals. We also used other templates to direct chlorination to C-17, where the cholesterol side chain is attached [41]. Further reactions permitted the removal of that side chain; a full paper summarized such aryl iodide template directed reactions in detail [42]. Subsequently we found that template methods could be used both to introduce oxygen at C-11 and to permit very effective removal of the steroid side chain [43]. Related to this, a tethered template with two chlorine binding atoms - a bipyridine or an iodophenylpyridine - was able to carry out the simultaneous chlorination of both C-9 and C-17, making approaches to corticosteroids even more attractive [MI. Later work [45] also permitted cleavage of the side chain so as to retain an acetyl group at C-17, and with a template tethered to the 6pposition of steroid 14 we were also able to chlorinate directly into the side chain at C-20, as an alternative method to product such 17-acetyl steroids by partial side chain removal. This work built on our earlier finding [46] that benzophenone photochemical insertion into the side chain could be achieved when the benzophenone was tethered to the p-face of the steroid. The findings, along with X-ray crystal structure data [46], made it clear that the nominally free rotation of the steroid side chain is in fact strongly restricted by steric constraints; the hydrogen on C-20 is pointed to the steroid p-face and requires a P-linked tether to permit its functionalization. Atoms other than iodine can also serve as chlorine binders in radical relay reactions. The sulfur atom of tethered diary1 sulfides can capture and relay a chlorine atom with predictable geometric control [47]. However, in contrast to the iodine atom templates, the sulfur templates could not capture and relay a chlorine from a free phenyliodochloride radical, only from the more reactive .S02Cl species produced when S02C12is the chlorinating reagent. Interestingly, phenyliodine dichloride was able to act as the chlorine atom source in a radical relay mechanism using the sulfur atom of a thioxanthone tethered template in 15 [48]. We also attached three steroid substrates to an iodophenyl template in 16 (Scheme 6-7) using a tris-silyl ether link, and saw that the template could direct selective radical-relay chlorination to all three tethered substrate species; in the same work we reported a simlar finding when a thiophene ring was the triply tethered template 1491. Thus the sulfur atom of thiophene can perform radical relay. In these triple catalytic functionali7ation\. the more reactive sulfuryl chloride was the preferred reagent.

168

6 Biomimetic Reactions Directed by Templates and Removable Tethers

13

0

0

15

Scheme 6-6 Radical relay functionalization in the synthesis of cortisone 13 and with a thioxanthone tethered template.

6.2 Biomimetic Reactions Using Covalently Linked Tethers und Teniplates

169

V

\

Si- 0-cholestanyl 0-cholestanyl

16

17

Scheme 6-7 Radical relay functionalization with a triply tethered template and with a tethered pyridine template.

Chlorine atoms would complex with benzene rings, but the geometry and stability were not sufficient to allow a simple phenyl group to be used as the relay template. The same was not true with pyridine rings. Radical relay processes were successful with tethered templates containing pyridine rings, as in 17. The process involved attachment of the relayed chlorine atom coordinated to the nitrogen atom and in the pyridine plane [50, 511. The results indicate that the pyridine-based tethered templates were superior to those based on aryl iodides or thioethers. Theoretical calculations and spectroscopic measurements indicate the nature of the complex between a pyridine ring and a chlorine atom [52]. Specifically, the chlorine atom is held to the pyridine nitrogen by a three-electron bond - two pyridine electrons, one chlorine odd electron - which with two bonding and one antibonding electron is weaker than an ordinary covalent bond, and thus able to transfer the chlorine atom to an available hydrogen attached to carbon in the radical relay process. A further study examined fused pyridine rings, in quinoline and acridine. 21stethered templates [53].Although the chlorine atom complex might have had a different structure

170

6 Biomimetic Reuctions Directed by Templates and Removable Tethers

from that of the simple pyridine complex, these fused pyridines were also effective templates for the selective chlorination of steroids. Some variants on the simple template-directed chlorination were also developed. For example, a steroid carrying a tethered iodophenyl group was chlorinated by electrolysis of a solution carrying chloride ion [54]. In this case, the electrolysis furnished C1, in solution to carry a radical relay process and electrolysis also initiated the radical process by one-electron oxidation of the iodophenyl group. As another variant, the radical relay mechanism requires that it be a chlorine atom that attaches to the iodine or pyridine or sulfur to abstract hydrogen, since a complexed bromine atom is not reactive enough, but the new bond to the substrate does not have to be a carbon-chlorine link. That bond is formed by untemplated attack of the substrate carbon radical on a reagent in solution and, with an appropriate sequence of tandem reactions, other atoms can be linked to the substrate. We showed that radical relay in the presence of phenyliodine dichloride but with an excess of CBr, afforded the bromosteroid, with bromine at the point that is normally chlorinated [55].When (SCN), was the additive, rather than CBr,, an SCN group was formed [55].The mechanism shown (Scheme 6-8) involves a bromine atom transfer to

+ Ph-I 12

O

W

'

+HCI -CBr3 +Ph-IC12

-

CBr3CI +Ph-ICI

Scheme 6-8 Mechanism of formation of a bromosteroid by radical relay functionalization.

6.2 Biomimetic Reactions Using Covalently Linked Tethers and Templates

171

the steroid radical to form the bromosteroid and .CBr,, but this radical then abstracts C1 from the solution PhICl, so as to form the phenyl iodochloride radical, which transfers its C1 to the template to permit hydrogen abstraction and complete the cycle. In the thiocyanate case it is the SCN radical that removes C1 from PhICl, in solution to permit a chlorine radical relay process. We have largely been describing reactions on steroid substrates, which are conformationally rigid and permit selective functionalizations by appropriate tethered templates. However, when the templates are linked to flexible chains, the results can be used to learn about the conformational preferences of such flexible chains. In one study [56], we examined the positional selectivities of insertion reactions into flexible chains by attached benzophenone units, a process we had also examined earlier [3 11, and compared the results with those from the intramolecular chlorination of such flexible chains by attached aryliodine dichlorides. The results were complementary. In another study [57] we used long-chain alkyl esters of nicotinic acid in radical relay chlorination, and saw some interesting selectivities reflecting conformational preferences in these nominally flexible cases. A study [58] on the use of non-tethered templates to direct the radical relay mechanism will be described in a later section of this chapter.

6.2.4 Selective Intramolecular Epoxidations Directed by Removable Tethers Sharpless [59] had extended earlier observations [60] on the selective epoxidation of the double bonds in allylic alcohols catalyzed by metals that coordinate to the hydroxyl groups. We decided to extend this by using a template to bring a coordinating hydroxyl group near in space to an otherwise remote double bond. Thus we showed that we could promote the epoxidation of a double bond in ring D of a steroid with a template temporarily attached to ring A in 18 (Scheme 6-9) [61]. The reaction was selective for such an accessible double bond even if the substrate had an additional double bond allylic to the point at which the template was attached. In the absence of the template, the allylic dou-

tBu-OOH

18

Scheme 6-9 Template directed epoxidation.

172

6 Biomimetic Reactions Directed by Templates and Removable Tethers

ble bond was epoxidized, while with the attached template, the remote ring D double bond was the reactive one. This template directed functionalization of double bonds within reach was also used to determine the conformational preferences of some terpene polyenes [62]. As in the previously described work with attached benzophenone reagents, the selective templatedirected epoxidations revealed the details of chain folding in flexible molecules.

6.3 Selective Reactions Directed by Non-covalently Linked Templates 6.3.1 Selective Aromatic Substitution Directed by Cyclodextrin Complexing The chlorination of anisole by HOCl in aqueous solution produces bothp- and o-chloroanisole, in a ratio of 60 :40 [63]. By contrast, in the presence of a-cyclodextrin (cyclohexaamylose) the para chlorination dominates, so that with 10 mM cyclodextrin the product is 96% p- and 4% o-chloroanisole. In water solution anisole binds into the cyclodextrin cavity. The simplest idea would be that this binding blocks chlorination at the ortho positions, which are inside the cavity, while the para position of the anisole is still exposed to solution. The true situation is more interesting. When the reaction shows 96% selectivity for para chlorination, the anisole is only 72% bound, so the bound anisole must be more reactive, not just more selective, than that in solution. The data indicate that ortho chlorination is indeed completely blocked for the anisolekyclodextrin complex, but that the para position is 5.6 k0.8 times more reactive in the complex than in solution. It was suggested that the chlorine was being delivered to the para position of bound anisole by a hydroxyl group of the cyclodextrin, which had been converted to a hypochlorite group (Scheme 6-10). Later work confirmed this idea. CI

alpha-cyclodextrin Scheme 6-10 Selective para-chlorination of anisole complexed by a-cyclodextrin.

In the full study [64], it was found that a lesser but similar effect was seen with /3cyclodextrin (cycloheptaamylose), which has a larger cavity in which anisole is both more weakly and more flexibly bound. Within this looser complex, orrho chlorination is

6.3 Selective Reactions Directed by Non-covalently Linked Templates

173

still completely blocked, but para chlorination has the same rate a5 it has in free solution. With 10 mM pcyclodextrin anisole is only 59% bound, not 72%, and the pardortha chlorination ratio becomes only 3.8: 1, not 21.6: 1 as with a-cyclodextrin. Thus, the catalysis of para chlorination in the a-cyclodextrin complex is promoted by rigid inclusion of the anisole into a tight-fitting cavity. Kinetic studies revealed something very striking: the rate of chlorination in the complex of anisole with a-cyclodextrin had a first-order dependence on HOCl, but in free solution the rate depended on [HOC1I2.Thus, different species perform the chlorination in the two situations. In solution it is known that the [HOCI]’ dependence indicates that the true chlorinating species is Cl2O, which is formed from two HOCl molecules. HOCl itself is too unreactive for the intermolecular chlorination to proceed rapidly, so the more reactive C1,O is used even though there is little of it. However, in the complex with cyclodextrin the HOCl rapidly and reversibly forms a hypochlorite ester with a cyclodextrin hydroxyl group, and this then delivers the chlorine atom to the accessible para position of bound anisole. An alkyl hypochlorite i s not a strong chlorinating agent, but the intracomplex character of the reaction makes the rate fast enough. As expected, the kinetic advantage of such an intracomplex reaction is greater with the tight anisole complex in a-cyclodextrin than with the looser complex in pcyclodextrin. The resemblance of this mechanism to that of the template directed chlorinations described previously is obvious: the OH group of cyclodextrin performs (non-radical) relay chlorine transfer from a solution reagent to the substrate. When p-methylanisole 19 (Scheme-6-11) was used as substrate, only the positions ortho to the methoxyl group were chlorinated, whether a-cyclodextrin was present or not, but reaction occurred only in free solution. Added a-cyclodextrin simply slowed the reaction by complexing the substrate. On the other hand, p-cresol20 was of course also chlorinated ortho to the oxygen substituent, but in this case the a-cyclodextrin accelerated the reaction. The polar hydroxyl group projects from the cavity so that the ortho positions are now within reach of a cyclodextrin hypochlorite group, and intracomplex chlorine delivery occurs. As a test of this mechanism, the coupling of p-benzenediazonium sulfonate 21 with phenol was examined. In solution it couples in the para position, but a-cyclodextrin N

19

20

21

Scheme 6-11 The chlorination of 19 and 20 and the coupling of 21 with phenol was investigated in the presence of a-cyclodextrin.

174

6 Biomimetic Reactions Directed by Templates and Removable Tethers

simply inhibits the reaction. The diazonium electrophile cannot be delivered by a cyclodextrin hydroxyl group, in contrast with such a delivery of a chlorine atom. One interesting feature of this work is that the enzyme chlorinase also can chlorinate anisole in water solution, but it gives a random mixture of ortho and para products [65]. Apparently the enzyme merely makes a chlorinating reagent, probably HOCI, and this then acts on the unbound anisole in free solution. However, the selectivity seen in our anisole complex chlorination is typical of that seen in other enzymes that do indeed direct reactions by geometric control within an enzyme-substrate complex. The anisole chlorination was examined further with two modified a-cyclodextrin derivatives [66]. In one we prepared the dodecamethyl derivative, in which all the primary hydroxyls and all the C-2 secondary hydroxyls of the a-cyclodextrin were blocked by methyl groups. This was an even more effective catalyst for the direct chlorination of anisole in its para position, and less than 1 % of orrho product could be detected with the catalyst at 10 mM. The extra methyl groups make anisole binding even stronger, accounting for the improved efficiency. Also, this work established that the C-3 hydroxyl group on the secondary face of the cyclodextrin could serve as the catalytic group in chlorine transfer. Of course, if the other hydroxyls were not blocked, as in the unmethylated catalyst, they might also serve to relay chlorine from solution to the bound substrate. In other work described in the same publication, a-cyclodextrin was converted to a solid polymer by reaction with epichlorohydrin, and this was used in a reactor to perform the flow reaction of anisole with HOCI. The product was completely para-chlorinated, and the reactor could be used repeatedly. Thus, the binding of substrate to an immobilized template has potential for practical synthesis with geometric control of selectivity. Since this early work, other laboratories have reported selective aromatic substitution reactions in cyclodextrin cavities. In most cases the cyclodextrin does not serve as a template, but simply blocks some otherwise reactive spots. These cases have been reviewed [301.

6.3.2 Photochemical Functionalizations by Complexed Benzophenones and Chlorinations Directed by Ion-paired Templates Benzophenone-4-carboxylic acid 22 complexes with other carboxylic acids in non-polar media by double hydrogen bonding. We examined the functionalization of hexadecanol by converting it to its hemisuccinate 23 and irradiating this in CCl, solution with benzophenone-4-carboxylic acid (Scheme 6-12) [67]. The products from insertion of the keto carbonyl group into the hexadecane chain were dehydrated and the resulting olefin was ozonized to afford, after saponification to remove the tether, a mixture of ketohexadecanols. The distribution reflected the conformational accessibility of substrate carbons in the tethered complex. Selectivity was seen when a similar process was performed on the hemisuccinate 24 of 3a,5a-androstanol. The only ketonic product, formed in 21% yield, was 16-keto3a,5a-androstanol 25, indicating a rather good selectivity at the most remote carbon from the point of attachment of the removable tether. Because the hydrogen bonding

6.3 Selective Reactions Directed by Non-covalently Linked Templates

175

Scheme 6-12 Photochemical functionalizations of alkyl and steroidal esters by complexed benzophenones.

association of reagent with the tether is reversible, the yield was improved by using an excess of reagent to drive the reaction to completion. Benzophenones carrying carboxylate groups attached para either directly or at the end of two-, three-, or four-methylene chains were used to functionalize sodium dodecylsulfate (SDS) and cetyl trimethylammonium bromide (CTAB) chains in micelles, with the hope that the micellar structure might fix chain conformations so that positionally selective functionalizations would occur [68]. It was seen that the chains in the micelles were flexible enough for several positions to be attacked by the triplet benzophenone unit, but very interesting conformational information was obtained. It was seen that the shorter benzophenone derivatives attacked further into the micellar chains, contrary to simple expectation. This indicates that the chains being attacked are curled back so that their nominally remote ends are actually closer to the micelle surface. This is apparently the way the chains can fill a spherical region: some chains extend all the way to the center of the micelle, while others curl back so as to fill the interchain spaces that would be created if all chains were fully extended. It is the latter curled chains that the benzophenone probes were attacking. Amphiphiles with two chains per head group can form vesicles, not simple micelles, and we used our probes to determine whether they had greater conformational order and could direct functionalizations more selectively [69]. We found that spherical vesicles showed evidence of conformational disorder comparable to that we had seen in micelles, but that flat vesicles showed considerable order, with attack largely at the expected dis-

116

6 Binmimetic Reactions Directed by Templates and Removable Tethers

tance from the surface if the chains were fully extended. Of course such probes may accentuate the amount of disorder in such systems, either by inducing the disorder or by reacting preferentially in disordered regions. However, the overall results of these studies indicated that we had interesting tools for probing structures of micelles and vesicles, but that the flexible chains were not well enough organized to permit synthetically useful selective functionalizations. To fix the geometries of flexible chains in such reactions, straight-chain a,o-dicarboxylic acids were used as substrates along with benzophenones that could bind to both carboxyl groups [70]. The benzophenones carried a binding group on the mera position of each ring, either trimethylammonium or carboxyl groups. The two cationic trimethylammonium groups in 26 stretched the chain of decanedioic acid dianion 27 across the benzophenone carbonyl, and directed 93%of the functionalization to the two equivalent central methylene groups of the substrate (Scheme 6-13). With the longer dodecanedioic acid there was more randomness, since the chain is not fully extended in the doubly ion-paired complex. The selectivity for the central carbons of the shorter octanedioic acid was slightly less, 8196, when it was complexed by hydrogen bonds to the benzophenonedicarboxylic acid. When there were only single linkage points in related molecules no functionalization occurred under the conditions used, so the double-ended complexing both promoted reaction and directed it selectively in the cases where the substrate and reagent had exactly the correct fit.

28

29

Scheme 6-13 The doubly ion-paired template 26 gives high regioselectivityin the photochemical functionalizationof 27, whereas the single ion-pairing substrates 28 and 29 are not functionalized with high specificity.

6.3 Selective Reactions Directed by Non-covalently Linked Templates

177

Ion pairing was also examined as a way to bind an iodophenyl template to a steroid to direct radical relay chlorination [58]. If successful, such a process could in principle use the template in only a catalytic amount. Cholestane carrying a 3a-trimethylammonium group (compound 28) was paired with iodophenyl sulfonates or carboxylates, and 3acholestanyl sulfate 29 was ion-paired with iodophenyl templates carrying trimethylammonium groups. Indeed, radical relay chlorination did occur with these templates, and not in appropriate control reactions, but the positional selectivities were not as great as with the covalently tethered templates described previously. Apparently ion pairing does not define the relative geometries of template and substrate well enough.

6.3.3 Oxidations Directed by Metalloporphyrin and Metallosalen Templates Heme (30), an iron porphyrin complex (Scheme 6-14), is the catalytic group in many oxidizing enzymes, including the cytochrome P-450s. Thus there has been a serious effort to mimic various aspects of these enzymes using metalloporphyrins. In the gener-

- O&-HpC-H&

rn 30

Me

0

0

32

Scheme 6-14 Catalytic epoxidation of 32 31 with 4 bound Cuz+

directed by coordination to the Cd”) complex 31 in the presence of an oxygen transfer reagent.

6 Biomimetic Reactions Directed by Templates and Removable Tethers

178

al scheme, an iron or manganese derivative of a synthetic porphyrin unit is used to catalyze the transfer of an oxygen atom from an oxidizing reagent such as iodosobenzene, hypochlorite ion, etc., to a substrate. With appropriate substituents to stabilize the porphyrins, some very high catalytic turnovers have been seen. Thus we set out to extend the geometric control ideas described above into this area. In our first study [71], we synthesized an iron porphyrin 31 carrying 8-hydroxyquinoline units at the four meso positions, and used Cu2+to bind substrate 32 carrying two nicotinate ester groups, one at each end (Scheme 6-14). The result was to stretch the substrate across the porphyrin so as to leave a double bond of the substrate directly above the iron in the porphyrin. We saw that the linkage of catalyst and substrate by their mutual binding to the Cu2+ions led to selective epoxidation of the bound substrates relative to analogous cases without such Cu2+ linkages. There was also catalytic turnover, as the bound product was replaced by more substrate. In the same publication, we also reported a similar study using the Mn3+complex 33 (Scheme 6-15) of the tetradentate ligand salen as the catalytic group. There were some differences from the porphyrin results, but auxiliary metal ions were also used to bind the catalyst and substrate in the salen case.

33

Me

3

N\

Me

Scheme 6-15 A metallosalen template for catalytic epoxidations.

Not all potential substrates can easily have nicotinate groups attached to both ends. Thus we set out to use hydrophobic binding into cyclodextrins in water as the mechanism for inducing formation of a complex between catalyst and substrate with geometric control and catalytic turnover. In the earliest work we have nonetheless attached groups to the substrates to solubilize them and promote their binding into cyclodextrins. We made porphyrins carrying four phenyl groups attached to the meso positions in which we were able to attach four P-cyclodextrin units to the para position of each phenyl(34), or two cyclodextrins attached to the para positions of neighboring phenyls (35) or of those on opposite sides of the porphyrin unit (36)(Scheme-6-16) [72]. The three

6.3 Selective Reactions Directed by Non-covalently Linked Templates

179

Beta-cyclodextrin

Scheme 6-16 Porphyrins 34-36 with appended p-

cyclodextrins catalyze the epoxidation of double bonds in substrates with hydrophobic termini which are bound in the cyclodextrin cavities.

180

6 Biomimetic Reactions Directed by Templates and Removable Tethers

porphyrin derivatives, as their Mn3+ complexes, were examined as catalysts for the epoxidation of double bonds in substrates that had hydrophobic ends to bind into cyclodextrin rings in water solution. We found that good catalysis and selectivity were seen when the catalyst camed two cyclodextrins on opposite sides of the ring (Mn'+ derivatives of 34 or 36), but not when they were on neighboring phenyls (Mn3+derivative of 35). Thus the prediction from molecular models that the substrates would be attacked only if they stretched across the porphyrin ring was borne out. For convenience, the catalyst based on 34 with four cyclodextrins was used for most of the studies, on the assumption that its productive complex was the one in which the substrates would bind to cyclodextrins on opposite sides so as to stretch the substrate across the porphyrin ring. As in the Cu2+ linked systems described above, we saw that there was selective turnover epoxidation of those substrates with hydrophobic ends that would bind to the cyclodextrins, These catalysts were then examined in the selective hydroxylation of saturated unactivated carbons in steroids [73, 741. Androstane-3,17-diol37 was converted to a diester 38 carrying tert-butylphenyl binding groups and sulfonate solubilizing groups, and oxidized in water solution with iodosobenzene catalyzed by the Mn3+-porphyrin39 carrying a P-cyclodextrin attached to the para position of four phenyls on the porphyrin meso positions (Scheme 6- 17). The steroid was hydroxylated only on the 6a-position to produce 40, and with about four turnovers. This was hydrolyzed to the androstanetriol 41. Control studies in which the tert-butylphenyl groups were not present on the substrate showed that there was no oxidation at all under the same conditions, so binding is required. A cholestanol carrying only one binding group was hydroxylated, but to a mixture of products. When the catalyst contained Fe2+rather than Mn3+similar results were obtained, but with much less turnover. Catalytic turnover is limited by the oxidative destruction of the porphyrin, and prior work showed how to diminish this problem. It had been found [75] that electron-withdrawing groups on the porphyrin carbons stabilized it to oxidation, and in particular porphyrins carrying pentafluorophenyl groups in the meso positions were much more stable than those with unsubstituted phenyls. Thus we synthesized a new catalyst 42 with fluorinated phenyls (Scheme 6-18) 1761. The synthesis was particularly convenient, since we found that the readily available porphyrin 43 carrying pentafluorophenyl groups on each meso position reacts with P-cyclodextrinthiol to replace a para fluorine in each phenyl ring, easily attaching a cyclodextrin in its place and forming 44. Its Mn3+complex 42 still showed the same selectivity as that of the unfluorinated compound, but now with 187 turnovers before the catalyst was destroyed. Further work is under way in this area. Substrates are being examined that directly bind with defined geometry into our catalysts, without the need to attach binding groups. Geometries are being varied in order to carry out other selective steroid hydroxylations, including those of direct pharmaceutical interest. Other oxidants, and still more stable catalysts, are being explored. Catalysts with more than two-point binding, and with an ability to hydroxylate unactivated carbons even in the presence of sensitive double bonds, are being examined. The potential of these biomimetic oxidizing catalysts seems quite substantial.

6.3 Selective Reactions Directed by Non-covalently Linked Templutes

181

do38

Me+

Me

Me

Scheme 6-17 Regio-

selective hydroxylation of androstane-3,17-diol (37) catalyzed by the Mn3+-porphyrin39 in the presence of iodosobenzene.

182

6 Biomimetic Reactions Directed by Templates and Removable Tethers

F

F

Scheme 6-18 The highly

stabilized catalyst 42 is readily prepared from 43 via 44.

6.3 Selective Reactions Directed bv Non-covulentlv Linked Tmn~lutes

183

The transfer of oxygen atoms by porphyrin catalysts is of course quite appealing, but it occurred to us some time ago that selective insertion of nitrogen atoms into substrates could also be useful, and accomplished in the same way. Thus we examined the nitrogen analogue of iodosobenzene, tosyliminoiodobenzene 45 [77]. It was able to insert the

tosylamine group into cyclohexane solvent to form 46, catalyzed by manganese or iron tetraphenylporphyrin (Scheme 6-1 9). In a collaborative study, it was found that even some isozymes of cytochrome P-450 were able to catalyze that reaction [78]. This work has stimulated others to take up the use of tosyliminoiodobenzene and related compounds for nitrogen functionalization reactions.

Me

Me

Scheme 6-19 N-atom transfer catalyzed by manganese or iron tetraphenylporphyrin.

6.3.4 Other Reactions Catalyzed by Coordinated Template Catalysts Intramolecular catalyses of cleavage reactions at carboxylic acid derivatives are well known, and outside the scope of this book. However, cleavage reactions can also be catalyzed by species that bind to the substrate and carry out a selective reaction that depends on the geometry of the mixed complex. Since this is in the spirit of the rest of what has been described, it will be briefly included here. Such reactions imitate enzymatic cleavage processes, so they are “biomimetic” in the same sense that selective functionalizations within mixed complexes are biomimetic [I]. The work using cyclodextrin binding has been extensively reviewed recently [30]. Esters can be cleaved by template catalysts that use a metal ion as both a binding group and part of the catalytic system [79-811. However, metal ion catalysis has also been extended to cases in which the principal substrate binding involves cyclodextrin inclusion; indeed, the first catalyst described as an artificial enzyme was such an example [82]. A cyclodextrin dimer 47 with a bound metal ion between the two cyclodextrins is a particularly effective hydrolytic catalyst for esters that can bind into both cyclodextrin units (Scheme 6-20) [83, 841. Esters can also be cleaved by reaction with the hydroxyl group of cyclodextrin within a complex [85-911. Some very high rates have been observed, and calculations account for the geometric preferences in such reactions.

184

6 Biomimetic Reactions Directed by Terndates and Removable Tethers

47

Scheme 6-20 Coordinated template catalyst 47 and cofactor analogues attached covalently to cyclodextrins in biomimetic catalysis.

Phosphate esters can be cleaved by template catalysts, especially those with cyclodextrin binding groups and linked catalytic groups. Catalysis of the hydrolysis of a bound cyclic phosphate by ribonuclease mimics has been extensively studied [92-981, as has catalysis by enzyme mimics carrying bound metal ions [99- 1021. When a coenzyme is linked to a binding group, sometimes with additional catalytic groups, interesting enzyme mimics result. A mimic carrying linked thiazolium ions 48 can perform reactions like those catalyzed in enzymes that use thiamine pyrophosphate [103, 1041, while mimics carrying pyridoxamine (49) and pyridoxal(50) units mimic the amino acid biochemistry that uses pyridoxal phosphate and pyridoxamine phosphate as coenzyme [ 105- 1151. Mimics of enzymes that use coenzyme B-12 have also been made [ 116, 1171, as well as aldolase mimics [118-1211. The double binding of substrates into two cyclodextrin rings that is involved in a number of catalytic systems has also been examined in itself, in studies directed at determining binding constants [ 122- 1241. Remarkably, the chelate effect that leads to very strong binding in these cases was found to be caused by an advantage in enthalpy, not entropy, relative to singly binding analogues [123]. The use of tethers and templates in the chemistry described above can furnish valuable information about the conformations of flexible molecules, and in appropriate cases can lead to selective functionalization reactions, including those at unactivated positions. Thus these reactions are “biomimetic,” imposing geometric control over the normal substrate reactivity control. It remains for the future to develop such reactions, and catalysts, to the point at which they take their place in the tools of synthesis for research and manufacturing. However, such progress seems likely,judging from the progress that has been made to date.

References

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Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes Frangois Diederich, Roland Kessinger

7.1 Introduction The synthesis of multiple adducts of CW has attracted much attention in recent years [ 11. Investigations of covalent derivatives with varying degrees and patterns of addition make it possible to explore how characteristic fullerene properties are affected by functionalization-induced changes in the conjugated n-chromophore [2]. Furthermore, higher adducts of c60 represent an unprecedented family of three-dimensional building blocks for molecular scaffolding targeting advanced fullerene materials and technologies [3]. The direct sequential multiple functionalization of the carbon sphere, however, is problematic in most cases, and isolation of a pure higher adduct usually requires tedious chromatographic isomer separation [4- 61. Moreover, a great diversity of interesting addition patterns is not accessible by sequential derivatization. Therefore, we proposed in 1994 a more general approach to the regioselective formation of multiple adducts of c60 by taking advantage of tether-directed remote functionalization techniques [7]. Such strategies had been initially developed by Breslow and co-workers for the selective functionalization of steroids and long-chain alkanes (see Chapter 6 ) [8]. Here, we illustrate how the application of non-covalent and covalent templates provides access to a great diversity of three-dimensionally functionalized fullerene building blocks. Templated synthesis now serves as a powerful tool for chemists interested in exploiting the outstanding technological potential of fullerenes and their covalent derivatives.

7.2 Anthracenes as Reversible Covalent Templates Among the most versatile reactions in fullerene chemistry is the Bingel cyclopropanation with 2-bromomalonate in the presence of base [9]. The problematics of regioisomeric product formation in nucleophilic additions to C,, is illustrated in the following, using this reaction as an example. By sequential double Bingel addition, Hirsch and co-workers obtained seven (1-7)out of eight possible bis-adducts named as cis-1-3, efaceand edge (these two bis-adducts are identical if the two addends are identical), and truns-I -4 (Scheme 7-1) [lo, 111, which could be separated by high-performance liquid chromatography (HPLC). Only the cis-1 bis-adduct was not formed in detectable quantities due to steric interactions between the addends which are forced into close proximity. The e (3) and trans-3 (5) bis-adducts are the major products in the sequential double addition,

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

190

which is kinetically controlled. The coefficients of the two nearly degenerate lowest unoccupied molecular orbitals (LUMO and LUMO + 1) of the monomethanofullerene, which are accepting the electron density from the incoming nucleophile, determine the product ratio of the bis-adducts. Theseorbitals have their highest coefficients at the e and trans-3 positions [12, 131.

cis3

A

trans-3

trans-1 B

00

.1-7

(cis-2); 0.9% (cis-3);2.5% (e); 15.5% (trans-4);3.7% (trans-3); 12.0% (trans-2); 5.3% (rrans-1);0.8%

Scheme 7-1 (A) Position notation for bis-adducts of c6, according to Hirsch et al. [lo]. (B) Products isolated from the second Bingel addition to bis(diethoxycarbony1)methanofullerene [C6,(COOEt),] [lo]. a) Diethyl 2-bromomalonate, NaH, toluene, 20 "C.

Upon further functionalization, the regioselectivity of the additions becomes remarkably enhanced. A third di(ethoxycarbony1)methano addend is preferentially introduced (40%) into the equatorial (e) position. Starting from e,e,e-tris-adduct, a remarkable sequence of stepwise e additions, with regard to the previous addends, affords hexakisadduct 8 [12]. This compound features a pseudo-octahedral addition pattern and can also be directly obtained in 14% yield by reacting C , with 8 equiv of diethyl2-bromomalonate/l,8-diazabicyclo[5.4.O]undec-7-ene(DBU) [121. Hirsch and co-workers subsequently discovered that the yield of hexakis-adducts such as 8 or 9 can be greatly increased and their separation from side products substantially facilitated, if 9,lO-dimethylanthracene (DMA) is used as a template (Scheme 7-2) [ 14, 151. Anthracene derivatives such as DMA are well known to undergo reversible Diels-Alder additions with fullerenes at ambient temperature [16- 181. After addition to the fullerene, the template directs diethyl malonate addends in the Bingel addition regioselectively into e positions, ultimately yielding the hexakis-adducts with a pseudo-octahedral, all-e addition pattern. The templated activation of e 6-6 bonds (bonds between two six-membered rings) is also efficient starting from C,, mono-adducts, and several examples are shown in Scheme 7-2. Thus, bis(alkyny1)methanofullerene 10 [ 191 reacted with diethyl2-bromomalonate/DBU (8 equiv) and DMA (12 equiv) to provide hexakis-

7.2 Anthracenes as Reversible Covalent Templates

191

adduct 11 in 28% yield [20]. Without a template, the yield was only 12% and the targeted product was contaminated with an inseparable impurity. Also, mono-adduct 12 was transformed in 35% yield into hexakis-adduct 13 [21], the precursor for the Pt" directed self-assembly of a dinuclear cyclophane of the molecular-square type [22], containing two appended fullerenes. Other examples for the use of this template activation method include the formation of hexakis-adducts 14-16 [ 14,23,24], with compound 16 providing an interesting example of a dendrimer with a fully buried fullerene core [25-271. X

DMA (10 equiv.), DBU (8 equiv.), c60

DMA (10 equiv.), DBU (20 equiv.), CH2(C02R)2(10 equiv.), c60

8 (23%) [ref. 141

BrCH(C02R)2(8 equiv.), PhMe, 20 "C

CBr4 (10 equiv.), PhMe, 20 "C, 12 h

-

8 (48%) [ref. 151 9 (40%) [ref. 151

Y

Y

10 Y = C w S i M e 3 ]

-

11 X = C(C02Et)2(28%) [ref. 201

13 X = C(C02Et)2(35%) [ref. 211

F=A

Y X

-

14 Y = N, X

14-16 XX = C(C02Et)Z

N ,

1.i:_]

15 Y = N",

16Y=C

N ,CH2C02Me N

0

[ref. 231 [ref. 231

[ref. 231

2

Scheme 7-2 Templated synthesis of hexakis-adducts 8 [14,15], 9 1151, 11 [20],13 [21],14 1231, 15 [23] and 16 1241 using 9,lO-dimethylanthracene (DMA) as a template. DBU = 1,s-diazabicyclo [5.4.0]undec-7-ene.

192

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

A spectacular example for a solid-state template effect was reported by Krhtler et al. [28]. In their elegant preparation of trans- 1 bis-anthracene adduct 17, the crystal packing provided the molding effect characteristic of a template. Heating a sample of crystalline mono-adduct 18 at 180°C for 10 min afforded 48% each of C,,, and bis-adduct 17, resulting from a topochemically controlled, regioselective intermolecular anthracenetransfer reaction (Scheme 7-3). The two anthracene addends in 17 were subsequently used as covalent templates in further solution conversions [29]. The two residues regioselectively directed four new malonate addends regiospecifically into the e positions, yielding hexakis-adduct 19. Thermal removal of the anthracene templates eventually provided tetrakis-adduct 20, with all four malonate addends aligned along an equatorial belt on the carbon sphere [29,30].

18

18

(48%)

DBU (40 equiv.), BrCH(C02Et)2(40 equiv.), L

CH2CI2,20 "C, 48 h

X

X

17 (48%) [ref. 281

190 OC, 5 min

-

X

X

X X

19 X = C(C0pEt)p (95%)

20 X = C(C02Et)z (88%)

[ref. 291

Scheme 7-3 Topochemical solid-state synthesis of bis-adduct 17 [28] and templated formation of tetrakis-adduct 20 [29].

7.3 Tether-directed Remote Functionalizations of C6,, Prior to the development of tether-directed functionalization methods, regioisomerically pure higher adducts of c60 usually were obtained by additions of transition metal complexes [31-331 or radical halogenations [34, 351. These reactions either occur under thermodynamic control or lead to the precipitation of the least soluble derivative. Isomerically pure higher adducts of c60 sometimes are also readily isolated out of more complex product mixtures [36]. Tether-directed remote functionalization of C,, allows the construction of fullerene derivatives with addition patterns that are difficult to obtain by thermodynamically or kinetically controlled reactions with free untethered reagents. Since the description of the first such reaction in 1994 [7], which is the subject of Section 7.3.1, an increasing variety of such regioselective functionalization protocols have

7.3 lethrr-directed Remote t;unc.tionulizations of C,,,

193

been developed, as documented in this overview. Of course, a tether-directed remote functionalization should only be called a template-directed reaction if the tether is removable, and this criterion is met by nearly all the examples described below. The benefits of these synthetic developments for the advancement of fullerene chemistry have been enormous. Thus, the availability of a great diversity of multiple adducts allowed a detailed investigation of the changes in the unique properties of parent c60 that occur with increasing degree of covalent functionalization and concomitant reduction of the fullerene chromophore [2,37-39]. Similarly, effects of the nature of the addition patterns and the nature of the addends on fullerene properties could be probed as well. Examples of properties that change profoundly upon increasing the functionalization of C60 are the facile reversible electrochemical reducibility [2,40,41], the efficiency in singlet oxygen photosensitization [2,42,43], or the reactivity of the carbon sphere against nucleophilic attack [2].Furthermore, higher adducts of C,, are finding increasing application in the construction of supramolecular advanced materials [3]. They also have been of great importance in the exploration of the different origins of fullerene chirality [44-461. In line with the topic of this monograph, the following chapters will mainly focus on the preparative aspects of tether-directed remote functionalizations and the reader is referred to the cited literature for more details on the physico-chemical investigations made possible by these synthetic methodology developments.

7.3.1 The First Tether-directedMultiple Functionalization of C,o: Formation of Higher Adducts with Novel Addition Patterns To achieve the regioselective formation of an e bis-adduct of Cm, methano[60]fullerenecarboxylic acid 21 as an anchor was reacted with the tether-reactive group conjugate 22 (Scheme 7-4)[7,47].The particular reactive group in conjugate 22 was chosen since 2substituted buta- 1,3-dienes are known to readily undergo irreversible Diels-Alder additions with c60 at 6-6 bonds [48].The design of the tether was based on molecular model examinations and semi-empirical PM3 calculations (PM3= parametric method 3) 149, 501 which suggested that mono-adduct 23, in which conjugate 22 had been attached to anchor 21, would readily differentiate in a Diels-Alder addition between the desired position eface(Scheme 7-1)and adjacent positions such as the cis-3,ee&., and trans-4 bonds. In these calculations, the selection criterion was the relative heat of formation of the various possible regioisomeric products; more elaborate computer modeling led to similar predictions I5 I]. Coupling of 21 to anchor 22 by esterification afforded the winered methanofullerene 23 which, upon heating, underwent the predicted Diels- Alder addition at the eface6-6 bond to give the rather insoluble, orange-brown C,-symmetrical bis-adduct 24 in 23% yield. Chromatographic analysis revealed that no other regioisomer had formed and that the rather low yield of 24 was due to a rapid '0,-ene reaction of the fused cyclohexene ring in the presence of light and 0,. with the fullerene derivative itself acting as efficient photosensitizer [52, 531. Fullerene derivatives with fused cyclohexene rings require careful handling under rigorous exclusion of light and air i n order to avoid this undesirable side reaction.

I94

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes reactive tether group

I i /+q=

HO

22

21

80°C

PhMe,

*

DCC, HOBT, DMAP, PhMe

23

24 (23%) [ref. 471

anchor J

group

25 DBU, PhMe, 20 "C c60

2. PhMe, 1 10°C, 39 h

26 (50%) [ref. 471

,anchor

27

1. DBU (1 equiv.), PhMe, 20 "C, 3 h

group

2. PhMe, reflux, 3 h

28 (60%) [ref. 471 BCH(C02Et)2 (5 equiv.), equiv.), PhCI, 20 OC

29 X = C(CO,Et), (72%)

30 X = C(C02Et)Z (73%)

Scheme 7-4 Preparation of bis-adducts 24 (7,471 and 26 [41,47] and tris-adduct 28 [7, 471 by tether-directed remote functionalization. A sequence of e attacks starting from 28 gives hexakisadduct 30 with a pseudo-octahedral addition pattern [7, 471. DCC = N,N"-dicyclohexylcarbodiimide, HOBT = 1-hydroxy-lH-benzotriazole, DMAP = 4-(dimethylamino)pyndine.

For the synthesis of a more soluble e bis-adduct, the preformed anchor-tether-reactive group conjugate 25 was attached in a Binge1 reaction to magenta-purple C , and subsequent heating of the formed wine-red mono-adduct in toluene for 39 h led to the desired brown product 26, which was isolated in 50% yield as the only regioisomer formed (Scheme 7-4) [41,47]. Similarly, conjugate 27 underwent the sequence of Bin-

7.3 Tether-directed Remote Functionalizations of C,,

195

gel attachment followed by double Diels-Alder addition at the two e positions on opposite sides of the carbon sphere to yield the orange-brown tris-adduct 28 in 60%yield with complete regioselectivity [47]. The C,,-symmetrical tris-adduct 28 can be readily prepared in multi-gram quantities; its addition pattern cannot be accessed by stepwise, non-tethered reaction sequences. Starting from tris-adduct 28, sequential malonate additions (excess of 2-bromomalonate, DBU) to e 6-6 bonds provided novel tetrakis-(29), pentakis-, and, eventually, yellow-colored hexakis-adducts such as 30 (Scheme 7-4) in which the fullerene n-chromophore is reduced to a benzenoid cubic cyclophane-type substructure [54]. The reactivity and physical properties of these higher adducts have been investigated in great detail [47, 55, 561; also, the corresponding endohedral 3He compounds were prepared and their n-electron ring-current effects studied by 'He-NMR WI. After advantage had been taken of the e-directing cyclohexene rings in the preparation of tetrakis- to hexakis-adducts, it was of interest to develop a method for removing these rings together with the p-xylylene tethers, thereby transforming the tether-directed remote functionalizationinto a true template-directed reaction. However, a direct removal of the cyclohexene rings in tetrakis-adduct 29 or hexakis-adduct 30 by retro-Diels-Alder reaction was not successful [57]. Therefore, an elegant alternative procedure, introduced by Rubin and co-workers [52,53], was applied. When a solution of 30 containing C , as lo2sensitizer was irradiated while a stream of 0, was bubbled through, the '02-ene reaction (the Schenk reaction [ 5 8 ] )at the two cyclohexene rings yielded a mixture of isomeric allylic hydroperoxides 31 with endocyclic double bonds (Scheme 7-5) [2,30]. Insitu reduction of 31 with PPh, gave a mixture of isomeric allylic alcohols 32 which was subsequently heated in toluene together with toluene-4-sulfonic acid (TsOH) and dimethy1 acetylenedicarboxylate (DMAD). Under these conditions, 32 was dehydrated to the corresponding bis(cyc1ohexa-1,3-diene) derivative which, via a Diels- Alder retroDiels- Alder sequence, afforded tetrakis-adduct 33 in 42% overall yield starting from 30. Transesterification with K,CO, in EtOH/THF yielded the octakis(ethy1ester) 20, which was characterized by X-ray crystallography. By a similar approach, the novel C,,-symmetrical tris-adduct 35 was prepared starting from pentalus-adduct 34 [2]. Compounds such as 20 are of interest since physical studies showed that the location of multiple allmethano addends along an equatorial belt, as in 20, leads to the smallest possible perturbation of the fullerene x-chromophore. Thus, the electronic properties of 20 do not differ much from those in C60whereas those of tetrakis-adducts with the functional groups placed all around the carbon sphere differ substantially from those of the parent fullerene [2, 301. Furthermore, tetrakis-adduct 20 provides a versatile intermediate for further molecular nanoscaffolding. It contains two reactive 6-6 bonds at the two poles activated by the four malonate addends in e positions around the equator. Thus, addition of 20 equiv of dialkynyl bromide 36 afforded hexakis-adduct 37 and, after deprotection, tetrakis-ethynylated 38 as an interesting novel building block for molecular construction

WI.

7 Regio- und Stereoselective Multiple Functionalization of Fullerenes

196

30

-

1. TsOH, PhMe, reflux, 4.5 h

Cm, PhCI,

R

2. MeO2C+CO2M;, 4.5 h, 47%

hv, 0 2 , 2 h

X

I.

PPh3, PhCI, 1 h, 20 "C

(mixture of constitutional and stereoisomers) 31 R=OOH K2C03, THF, 33 R = Et, R' = 32 R = OH (90%) EtOH, 3.5 h, L 20 R = R' = Et 80% X = C(C02Et)Z

ROAO 6 OR [ref. 21

E

1. hv, 0 2 , Cm, PhCI, 2 h 2. PPh,, PhCI, 3 h 3. DMAD, TsOH, PhMe, A, 5 h EtO

X

35 (34%) [ref. 21

34 X = C(C02CH2COZEt)2

t

EtO

0

Me3Si SiMe3 36 (20 equiv.), CHZCl2,Me2S0, DBU (20 equiv.)

20

Et

0

4. K2CO3, THF, EtOH, 3.5 h

-

TBAF, THF, 1.5 h, 20 "C, 84%

[ref. 571

K 37 R = SiMe3 (32%) 38 R = H

X = C(C02Et)Z

Scheme 7-5 Removal of the cyclohexene moieties and p-xylylene tethers in 30 and 34 provides tetrakis-adduct 20 12, 301 as precursor to the tetraethynylated hexakis-adduct 38 [57] and trisadduct 35 [2], respectively.

7.3.2 The Bingel Macrocyclization The simplest, most versatile method for the preparation of covalent bis-adducts of c60 with high regio- and diastereoselectivity is the macrocyclization between c60 and bismalonate derivatives in a double Bingel reaction (Scheme 7-6) [25, 59, 601. As a general protocol, diols are first transformed into bis(ethy1 malonyl) derivatives. Subsequent-

7.3 Tether-directed Remote Functionalizations of C,,

197

ly, the corresponding bis(bromoma1onate)s are prepared and subjected to the Bingel reaction with C,, in toluene in the presence of DBU (variant A). By the even shorter variant B, bis(iodoma1onate)s are prepared in situ [59, 621, and the one-pot reaction of C,,, bis(ethy1 malonate), and DBU in toluene at 20 "C generates the macrocyclic bis-adducts in yields usually between 20 and 40% and high regio- and diastereoselectivity.

Variant A DBU, THF, 0 to 20 "C, CBr4 c60, DBU, PhMe 20 "C

Variant B

Scheme 7-6 General protocols for the Bingel macrocyclization reaction [25,59,60].

(0

equiv), DBU, PhMe, 20 "C

c60 (2.5

40

0A0vsiEt3 +

39 (CZ, 33%)

(+41 (C1,16%) [ref. 601

Scheme 7-7 First observation of the Bingel macrocyclization reaction [60].

198

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

E

42 (c, 33%) [ref. 591

43 (C,22%) [ref. 251

cis4

Et

(S,S,'A)-44(C2,20%) d.e. > 97% [ref. 641

(R,R,'C)-44 (C2,24%) d.e. > 97% [ref. 641 e

0 Et

45 (C1, 44%) [ref. 251

trans4

(i)46 (C1, 44%)

[ref. 251

nnnn

0 0 0 0 0

47 ( t C,, 9Yo) [ref. 251

(3-48(C1, 22%) [ref.651

Scheme 7-8 Examples of C,, bis-adducts directly produced by the Binge1 macrocyclization reaction (Scheme 7-6). For each compound, the molecular symmetry and the preparation yield are given.

7.3 Tether-directed Remote Functionalizations of C,,

(349 ( C,,

(350

20%) b o u t [ref. 251

trans-2

trans-7

(C2, 15%) [ref. 661

( C2, 5%) out-out [ref. 251 Ph

(5)-52 (Cz, 41%) [ref. 671

(3-51 (Cz, 1.5%) [ref. 661

(*)-!j3

199

Rh

54 (Ca,17%) [ref. 681

Scheme 7-8 (Continued).

The Bingel macrocyclization was first observed during attempts to prepare poly(triacetylene) oligomers [63] with laterally pendant C60 spheres as advanced materials with promising electronic and optical properties. When (E)-hex-3-ene- 1 S-diyne 39, a direct precursor, after silyl group deprotection, to the desired PTA oligomers, was prepared by double Bingel reaction between two , C molecules and bis(bromoma1onate) 40, the cyclophane-type C1-symmetrical cis-2 bis-adduct (*)-41, resulting from Bingel macrocyclization, was obtained with complete diastereoselectivity as a significant side product (Scheme 7-7) [59, 601. This observation led to a first comprehensive study [60] which demonstrated the enormous versatility of the new tether-directed bis-functionalization. With the exception of cis-1, all possible bis-addition patterns (Scheme 7-1) have been

200

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

obtained today and some interesting examples (42-54) [25, 59,60, 64-68] for the various functionalization patterns are presented in Scheme 7-8.

7.3.2.1 Formation of cis-2 bis-adducts In theory, each macrocyclic isomer could be formed as a mixture of diastereoisomers, depending on how the EtOCO residues at the two methano bridge C-atoms are oriented with respect to each other (in-in, in-out, and out-out stereoisomerism) [69]. However, with the exception of the in-out isomer (2)-49 (Scheme 7-8), out-out stereoisomers have been obtained exclusively until now. The out- out geometry of cis-2 bis-adduct 42 with an o-xylylene tether was proven by X-ray crystallography [59]. The Bingel macrocyclization has been increasingly exploited in the construction of molecular building blocks for supramolecular systems. For this purpose, cis-2 bisadducts, such as 43 with a m-xylylene tether (Scheme 7-8), have been particularly useful. Thus, bis-adducts 55 [70], a fullerene-glycodendron conjugate, and 56 [71] were shown to form stable Langmuir monolayers at the air-water interface (Scheme 7-9).

A

57 [ref. 251

58 R = C12H25[ref. 751

Scheme 7-9 Examples of functional supramolecular systems containing C ,, cis-2 bis-adducts prepared by the Bingel macrocyclization.

7.3 Tether-directedRemote Functionalizations of C,,

20 1

59 R = C8Hl7 [ref. 731

Scheme 7-9 (Continued).

Other examples include the fullerene dendrimer 57 [61] with a molecular mass of 7344 Da, dendrimer 59 featuring a bis( 1,lO-phenanthroline)copper(II) core and 16 peripheral fullerene groups (molecular mass 31601 Da) 172,731, and porphyrin derivatives with two [74] and four (58) [75] appended fullerenes. Higher adducts are also accessible in a regiospecific way. Thus, starting from cis-2 bis-adduct 61, which was prepared by Bingel macrocyclization of 60, a clipping reaction yielded tetrakis-adduct 62 with an all-cis-:! addition pattern along an equatorial belt (Scheme 7-10) [25].It is evident that by a judicious combination of tethers, a rich variety of higher adducts of Cm with original addition patterns should become accessible. A first example suggests that the malonates can also be replaced by other groups. Thus, the tethered bis(P-keto ester) 63 was used to prepare the cis-2 bis-adduct 64 [76a] and the addition of tethered bismalonamides found application in the formation of a fullerenecalixarene conjugate [76b]. It is clear that the full scope of the Bingel macrocyclization remains yet to be explored.

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

202 THPO,

P o

0-

1. TsOH .H20, EtOH,

PhMe, 80 "C

2. Et02CCH2COC1, C~HSN, CH2C12, 0 o c -> 20 "C 3. DBU, 12, PhMe, 20 "C

61 (Cs, 38%)

THP~

63

62 (C,, 16%) [ref. 251

64 (C, 13%) [ref. 76a]

Scheme 7-10 Extensions of the Bingel macrocyclization: preparation of a higher adduct of CW [25] and use of tethered bis(pketo esters) instead of tethered bismalonates [74]. THP= 3,4,5,6tetrahydro-2H-pyran-2-yl.

7.3.2.2

Formation of cis3 bis-adducts

Since cis-3, trans-3, and trans-2 bis-adducts of , C with identical addends are chiral as a result of inherently chiral functionalization patterns [lo, 44-46], it was of interest to explore whether Bingel macrocyclizations with bismalonates bridged by non-racemic tethers would provide an enantioselective synthesis of these compounds. An overall enantioselective synthesis of optically active C60 bis-adducts had been achieved previously by asymmetric Sharpless bis-osmylation [77]; however, this sequential bis-functionalization lacks the regioselectivity of the Bingel macrocyclization, and therefore requires tedious regioisomer separations. A sequence of a highly diastereoselective Bingel macrocyclization using a non-racemic tether, followed by removal of the tether via transesterification, indeed provided an enantioselective synthesis of optically active cis-3 bis-adducts in which the chirality results exclusively from the addition pattern [25,46, 591. Starting from (R,R)-65 and (S,S)-65,which were prepared from the corresponding optically pure diols, the two enantiomeric cis-3 bis-adducts (R,R,fA)-66and (S,S,fC)-66 were obtained with high diastereoselectivity (diastereoisomeric excess d.e. > 97%) (Scheme 7- l l). In each macrocyclization, two diastereoisomeric out-out cis-3 bis-adducts are possible due to the chiral addition pattern; however, the high asymmetric induction by the optically active tether in the second intramolecular Bingel addition led to the formation of (R,R,fA)-66

7.3 Tether-directedRemote Functionalizations of C,,

203

and (S,S,fC)-66 only. The simple stereochemical descriptors 'C and 'A (f = fullerene, C = clockwise, A = anticlockwise) have been introduced to specify the configurations of chiral fullerenes and fullerene derivatives with a chiral functionalization pattern [44]. Similarly, the cis-3 adducts (R,R,fC)-44and (S,S,'A)-44 (Scheme 7-8) were formed with a d.e. exceeding 97% (HPLC) starting from the corresponding optically active tethered bismalonates 1641. Transesterification of (R,R,fA)-66and (S,S,fC)-66 yielded the cis-3 tetraethyl esters (fA)-2 and (fC)-2 with an enantiomeric excess (e.e.) higher than 99% [(fA)-2]and 97% [(fC)-2](HPLC), reflecting the e.e.s of the corresponding commercial starting diols. The absolute configurations of these optically active fullerene derivatives could be assigned from their calculated circular dichroism (CD) spectra [46]. The fact that the tethers in (R,R,fA)-66and (S,S,fC)-66could be readily removed by transesterification makes them true covalent templates.

OEt (R,R)-65

(R,R,'A)-66(G, 15%)

(1A)-2 (G, 83%) [ref. 591

&OEt

K2Co3, EtOHTTHF, r.t., 1.5h

___)

-O*'OEt OEt (S,S)-65

(S,S,'C)-66 (q, 13%)

fC)-2(q, 40%) [ref. 591

Scheme 7-11 Enantioselective synthesis of ( fA)-2 and ( fC)-2by diastereoselective tether-directed bis-cyclopropanation of Cm, followed by transesterification [25,46,59].

Of substantial interest were the chtroptical properties of these enantiomeric C60derivatives with chiral functionalization patterns: the mirror-image CD spectra of ('C)-2 and (fA)-2displayed large Cotton effects between 250 and 750 nm with A& values approaching 150 cm2 mmol-' 125,591.These intensities of the CD bands are of similar magnitude to those measured for inherently chiral fullerenes (such as 02-C76[78] and their derivatives [79])but are much larger than those measured for non-racemic fullerene derivatives in which the chirality only results from the addends 1251.

204

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

7.3.2.3 Other bis-functionalization patterns The e bis-adducts 45 (Scheme 7-8) and eat-45 (not shown) provide examples for optically active fullerene derivatives in which the chirality originates only from the optically active tether, and the intensities of their CD bands ( A s values c 30 cm2 mmol-') are smaller than those of (fC)-2and (fA)-2(Scheme 7-1 1) with inherently chiral functionalization patterns [25]. The Bingel macrocyclization is not completely regioselective in each case [25,59].As an example, the use of a tether derived from 1, IO-phenanthroline-2,9-dimethanolyielded both e bis-adduct (k)-46 and trans4 bis-adduct 47. By the Bingel macrocyclization, organic chromophores or receptor sites can be precisely positioned in close proximity to the fullerene surface, thus offering the potential for inducing changes in the physical properties of the carbon allotrope. This was exploited in the construction of the &,-containing catenane (+)-67 4PF6 starting from the trans4 crown ether (+48 [65].The formation of (+)-67.4PF6 by self-assembly, following the elegant strategy developed by Stoddart and co-workers [80], is depicted in Scheme 7-12. With the fullerene moiety acting as an electron acceptor, (+)-67.4PF6features an unprecedented intramolecular A-D-A-D-A stack (A = acceptor, D = donor).

-

CQ-,,

Br

I

DMF, NHdPF6,lO d

(f)-48

(+67 4PF6 (C,, 18%) [ref. 651

Scheme 7-12 Preparation of (*)-67 -4PF, by self-assembly [65].

The Bingel macrocyclization with a bismalonate bridged by a large tether derived from 2,9-bis[4-(hydroxymethyl)phenyl]-1,10-phenanthroline provided, as already mentioned in Section 7.3.2.1, the only example so far of the formation of both stereoisomeric in-out trans-3 ((9-49)and out-out trans-3 ((2)-50) bis-adducts [25]. Steric considerations based on molecular model examinations and computer modeling indeed had indicated that the large tether would lead to the formation of the two diastereoisomers with similar calculated steric strain energy. The formation of in-out (?)-49 was fully confirmed by transesterification under cleavage of the tether leading to the known tetraethyl ester (+5 [lo].

7.3 Tether-directedRemote Fiinctioiiali,-atic?ii.r of C,,,

305

Substantial perturbations of the electronic structure of the fullerene were observed when an alkali metal cation was bound to the crown ether moieties in tt-trn.s-2bij-adduct (+)-51 or trans-1 bis-adducts (-+)-53 [66]. In these compounds, the crown ether receptor site is positioned closely and tightly on the fullerene surface. Upon complexation of alkali metal ions to this site, the first fullerene-based electrochemical reduction process becomes significantly facilitated due to the stabilization of the formed fullerene radical anion by the cationic center bound in close proximity. This was the first ever observed effect of cation complexation on the redox properties of the carbon sphere in fullerenecrown ether conjugates [81-861. By transesterification of (+)-53 with Cs,CO, in anhydrous 1-hexanol/THF, the tether was removed under formation of the corrcjponding D,,-symmetrical tetrakis(hexy1 ester) (34%) [66], thereby providing a versatile entry into diverse molecular scaffolding using trans- 1 bis-adducts from C,o. Porphyrin-fullerene conjugates attract wide attention for their intramolecular energy and electron transfer properties [87, 881. By attachment of the porphyrin to two points on the c60 surface, the interchromophoric spatial relationship in the cyclophane-type molecular dyads trans-2 (+)-52 [67] and trans-l 54 [68] (Scheme 7-8), which controls both energy and electron transfer, is rigorously defined. In the two systems, as well as in the fullerene-porphyrin conjugate 58 [75] (Scheme 7-9), the close proximity between fullerene and porphyrin chromophore leads to a nearly complete quenching of the porphyrin luminescence, presumably as a result of efficient energy transfer between the porphyrin donor and the fullerene acceptor.

7.3.3 Formation of Bis-adducts by Double Diels-Alder Addition of Tethered Bis(buta-1,3-diene)sto C,,, The double Diels-Alder addition [89,90] of a tethered bis(buta-1,3-diene) to C,,, has been used for the regioselective formation of a trans-1 bis-adduct by Rubin and his group in their highly original program targeting the creation of large holes in the shell of c60 and the formation of endohedral metallofullerenes [9 I]. These researchers prepared the tethered bis(cyc1obutene) 68 as a mixture of stereoisomers (Scheme 7-13). Upon refluxing 68 with c6, in toluene, ringopening of the cyclobutenes occurred and the resulting 1,3-diene underwent cycloaddition regioselectively to afford the trans- 1 derivative 69 in 30% yield. Upon treatment with TsOH, the tether is eliminated under formation of a fullerene containing two fused cyclohexa- 1,3-dienes, which each undergo a rearrangement sequence [92] consisting of a photochemical [4 + 41 cycloaddition followed by a thermal [ 2 + 2 + 21 retro-cycloaddition to yield the mixture of stereoisomers 70 and 71 which have not yet been separated. Nishimura and co-workers used bis(o-quinodimethanes) connected by a, mdioxamethylene tethers for the regioselective bis-functionalization by double Diets-Alder addition (Scheme 7-14) [93]. The tethered bis(o-quinodimethanes) were intermediately formed by heating the bis(bromomethy1) derivatives 72a-d together with C,,, i n toluene in the presence of KI and [18]crown-6 [90]. With an 0-(CH,),-0 tether (72a). the cis-2 and cis-3 bis-adducts 73a and (2)-74a were isolated in 10% and 8% yield, respec-

206

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

68

69

TsOH, hv, PhMe. reflux

69 (30%) [ref. 911 (mixture of diastereoisomers)

H Ph

H

* Ph

70 (CA

+

H Ph

[ref. 911

(4-71 (C2)

(52% (70 + ( 3 - 7 1 ) )

Scheme 7-13 Preparation of trans-1 bis-adduct 69 and elimination of the tether followed by rearrangement to the mixture of stereoisomers 70 and (*)-71 [91].

tively. Compound 72b,with an O-(CH2)3-0 tether, showed a higher regioselectivity,and the cis-2 bis-adduct 73b was isolated in 20%yield in addition to cis-3 bis-adduct (9-74b as a minor product (9% yield). Interestingly, the reaction of 72c,with an 0-(CH,),-0 tether, displayed hardly any regioselectivity whereas the conversion of 72d,with the longest 0-(CH,),-0 tether, proceeded with high regioselectivity and yielded the e bisadduct (+)-75in 30% yield with the yield of other regioisomers, which were not isolated, not exceeding a total of 2-3%. The tethers were subsequently readily removed by ether cleavage with BBr, in benzene, providing the corresponding bis(pheno1s) 76,(+)-77,and (+)-78in nearly quantitative yield. The racemic mixtures (2)-74a, (9-74b,(2)-77,and (+)-78were successfully resolved by HPLC on a chiral stationary phase (CHIRALCEL OD@)[94]. In agreement with other findings [25,45,59], the CD spectra of non-racemic 74a and 77 featured very intense Cotton effects due to the strong chiroptical contributions of their chiral functionalization patterns. In contrast, the functionalization patterns in 74b and 78 are achiral and their enantiomers displayed much weaker CD bands. With tetrabromide 79,featuring an optically active tether, the double Diels-Alder addition yielded one single diastereoisomeric cis-3 bis-adduct, presumably 80, with complete diastereoselectivity besides cis-2 bis-adduct 81 as the major product (Scheme 7-14). An interesting templated bis-functionalization was reported by Shinkai and coworkers, who introduced two boronic acid groups regioselectively via Diels-Alder addition onto the fullerene using saccharides as “imprinting” templates (Scheme 7-15) (for the concept of molecular imprinting, see Chapter 2) [95,96]. The formation of cyclic boronate esters between boronic acids and carbohydrates has in recent years been elegantly applied by Shinkai and his group to carbohydrate recognition, transport, and sensoring [97]. They now use saccharides as templates to “imprint” into the surface of

7.3 Tether-directed Remote Functionalizations of C,,

207

fullerenes two boronic acid groups, with their relative position on the surface of the carbon sphere being directly related to the structure of the templating saccharide. After cleavage of the boronate esters, the resulting bis(boronic acid)-substituted fullerene should provide a specific recognition site for the sugar that served as the initial sugar template.

c60

KI, 18-crown-6, PhMe, A

72a,b

I

I

I

I

\

'BrB?

72a n = 2 72bn=3 Br 7 2 c n = 4 72dn=5

72a,b n

(*)- 75 n = 5 (C1,30%)

7h/7=2(C910%) (*))-7&n=2(&,8%) 73bn=3 (Cs,20%) (+)-74bn=3 (G,9%)

H

H

76 (C, quant.)

79

(*)- 77 (Cz, quant.) [ref. 931

H

(3-78 (Cl, quant.)

80 (G, 3%) most plausible

81 (Ci, 10%) [ref. 941

Scheme 7-14 Regioselective bis-functionalizationsby double Diels- Alder addition of tethered bis(o-quinodimethanes)to C60[93,94].

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

208

Br

HO, ,OH B

82

Br

86

(C,56%)

18-crown-6,

HCI, THF

PhMe, reflux

85 ( C,,42%) [ref. 951

87 (CJ

Scheme 7-15 Regioselective bis-functionalization of C , using a saccharide as imprinting template [95,96].

Thus, compound 82 containing 3-O-methyl-~-glucofuranose as a template underwent a double Diels-Alder addition with C,, providing as the major product the trans4 bisadduct 83 [95]. Removal of the saccharide template yielded boronic acid 84, which is a potentially selective receptor for the initial template saccharide molecule. Preliminary recognition studies indeed showed that 84 retains the memory for the initial template. Protection of the boronic acid residues afforded 85 (42% yield, HPLC) which was transformed into diol 86 by treatment with H202. Scheme 7-15 shows the structure of an alternative trans-4 diol87 with C, symmetry that could potentially also be formed in the reaction sequence starting from 82; an unambiguous assignment of the exact structure of 83 and the following bis-adducts 84-86 remains yet to be reported. There is little doubt that the concept of molecular imprinting in homogeneous solution on surfaces such as those of a fullerene bears exceptional fundamental and technological potential.

7.3 Tether-directed Remote Functionalizations of C,,

209

7.3.4 Double [3+21 Cycloaddition of Tethered Vinylcarbenes Nakamura and co-workers synthesized the oligomethylene-tethered bis(cyc1opropenone acetals) 88a-c to generate by thermolysis minute amounts of nucleophilic vinylcarbenes which subsequently underwent two-fold [3+2] cycloadditions to 6-6 bonds of C6() (Scheme 7-16) [98,99]. Thus, reagent 88a, with a -(CH2)3- tether, afforded the C,-sym-

88bn=4 88cn=6

A

A

8% (C, 14%)

A,A=

or)<Me

1

Me

A,A=

acidic hydrolysis

91 (quant.) A,A=

90 (c, 23%)

=O

1

89b (Cs, 16%) A,A=

Me

92 (quant.)

A,A =

Me

[ref. 98,991

=O

A,A=

Me

(*)- 93 (Cp, 41%)

MeYMe Me Me sieves (4 A), molecular

""\OxMe

MeKzd-..

0 Me

1,2-C12CGH4, 72 h, 150 OC

* 4,A = A,A

Mee ' L d M 94

Me

95 (cz,17%)

Scheme 7-16 Regioselective bis-functionalization by double [3 + 21 cycloaddition of tethered vinylcarbenesto C, [98,99].

210

7 Regio- and Stereoselective Multiple Functionalization of Ful1erene.v

metrical cis-1 bis-adduct 89a in 14% yield together with the C,-symmetrical cis-2 bisadduct 90 which was formed as the major regioisomer in 23%yield. Upon acidic hydrolysis of the acetal groups, the corresponding diketones 91 and 92 were obtained in quantitative yield. Interestingly, 88b, with the longer -(CH.J4- tether, provided the C,-symmetrical cis- 1 bis-adduct 89b as the only formed regioisomer in 16% yield. Apparently, the conformational strain of the tether moiety in the transition state of the second addition, rather than product stability, controls the regioselectivity of the attack, and computational studies were undertaken to elucidate the origin of this selectivity [99]. The reagent with the longest -(cH2)6- tether, 88c, afforded in high yield (41%) the C2-symmetrical cis-3 bis-adduct (k)-93,which could also be quantitatively transformed by acid hydrolysis into the corresponding diketone. Preliminary results obtained with 94, with an optically active tether, showed that a single non-racemic cis-3 stereoisomer (95) was obtained in a highly diastereoselective way.

7.3.5 Double [3+21 Cycloadditions of Tethered Bis-azides The addition of azides, followed by extrusion of dinitrogen, leading to aza-bridged fullerenes, provides a versatile method for the functionalization of c 6 0 . Numerous reports have appeared since this conversion was first described in the literature [ 1001, and the reader is referred to a recent review by Hirsch [ 1011. In order to control the regioselectivity of bis-adduct formation, tethered bis-azides have been used by Luh and coworkers (Scheme 7-17) [102-1041. When bis-azides 96a/b, tethered by a -(CH2)z- or -(CHJ3- bridge, were reacted with c60, bis-aza-fullerenes 97a/b were obtained in which two aza bridges are positioned at two open 6-5 junctions of a fluorene moiety of c60 (Scheme 7-17) [ 1021. When c 6 0 was treated with 2,2-dibenzyl-l,3-diazidopropane (98) in refluxing chlorobenzene for 8 h, the three products 99,100, and 101 were isolated in 18, 24, and 11% yields, respectively 11041. Whereas compound 101, similarly to 97, possesses two aza bridges at the open 6-5 junctions of a fluorene moiety in c60, the structures of the two other compounds are remarkably different. The bis-azide had undergone [3+2] cycloaddition to two neighboring 6-6 bonds in a six-membered ring (cis-1 addition pattern) to yield 100. Compound B also features a cis-1 addition pattern with two fused aziridine rings at neighboring 6-6 bonds in a six-membered ring. Thermolysis of 100 in refluxing benzene gave a 40 :54 :6 mixture of 99,101, and c60,respectively, in quantitative yield, clearly showing that compound 100 is an intermediate in the formation of 99 and 101. Mechanisms for these interesting conversions were proposed by Luh and co-workers [105]. Finally, the reaction of c60 with the optically active bisazides 102a/b yielded the enantiomerically pure bis-aza-fullerenes 103a/b with an addition pattern as in 97a/b [103].

7.4 Conclusions

A ' n

PhCI, reflux

~

@412,"

N3 N3

-

96a (n = 1) 96b (n = 2)

97a (n = 1, C,, 53%) 97b (n = 2, C,, 31%)

021

Bn

N 3BnYBn N 3

(1.5equiv.)

211

[ref. 1041

100 ( C,, 25%)

98

101 (Cs1l%)

R Me Me4 0-c.

Me R

%Me

r O

6

Me

PhCI, reflux,

--

6-8 .. h

N3 N3 (1.5 equiv.) 102a (R = Me) 102b (R = Ph)

* 0 Me

[ref. 1031

TR

Me 103a (R = Me, Cl, 54%) 103b (R = Ph, C1,56%)

Scheme 7-17 Regioselective bis-addition of tethered bis-azides to C6,,[102- 1041.

7.4

Conclusions

Templated synthesis approaches are currently revolutionizing the covalent chemistry of fullerenes. They provide elegant, imaginative protocols to highly functionalized fullerene building blocks for three-dimensional molecular scaffolding. There is much room for innovation in this emerging area. The variety of reactions that can be used to attack the fullerene is large and the number of structural and functional templates seemingly unlimited. A particularly exciting aspect of this research is related to the high stereoselectivity observed in the preparations of chiral cis-3 bis-adducts described above. With non-racemic tethers acting as chiral auxiliaries, highly diastereoselective bis-additions

212

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

occur and, after tether removal, overall enantioselective syntheses of doubly functionalized fullerenes are accomplished. It is becoming clear that the curved surface of the carbon sphere imposes substantial stereoelectronic restraints which restrict the number of energetically favorable reaction pathways and transition states in tethered bis-functionalizations. By imprinting the precise alignment of functional groups and ligands for metal ions onto fullerene surfaces, new generations of reagents and catalysts for asymmetric reactions in homogenous solution may emerge. Covalent derivatives of fullerenes promise fascinating applications as advanced materials in diverse advanced technologies such as energy and information storage and transport, sensorics, or microfabrication. Only the continued invention of functionalization methodology such as that described in this chapter will ensure that these desirable objectives are reached in the future.

7.5 Experimental Procedures 7.5.1 Preparation of Hexakis-adduct 11 using DMA as a Template (Scheme 7-2) [20] A solution of 10 [19] (145 mg, 0.156 mmol) and DMA (323 mg, 1.56 mmol) in dry toluene (14.5 mL) was degassed and subsequently stirred at 20°C for 2 h. Diethyl 2bromomalonate (210 yL, 1.24 mmol) and DBU (280 yL, 1.87 mmol) were successively added, and the dark red solution was stirred for 5 d at 20 "C, then diluted with CH2C12 (100 mL), washed with H,O (3x 10 mL), and dried (MgSO,). Evaporation of the solvent, flash chromatography (2x; SiO,H, cyclohexane/AcOEt 7 : 3, then SiO,, CH2C12/ cyclohexane 4 :1) gave 11 (75 mg, 28%) as a yellow solid. M.p. > 240 "C.

7.5.2 Preparation of Bis-adduct 24 by Reaction of Methano[60]fullerenecarboxylic Acid 21 with the Tether-Reactive-group Conjugate 22 (Scheme 7-4) [47] To 21 (100 mg, 0.128 mmol) in PhBr (20 mL) was added sequentially DCC (26.5 mg, 0.128 mmol), HOBT (17.4 mg, 0.128 mmol), DMAP (15.7 mg, 0.128 mmol), and 22 (48.4 mg, 0.256 mmol). After stirring at 20 "C for 19 h, the mixture was loaded directly onto column and chromatographed (SiO,, PhMe/hexane 2 : I), yielding a wine-red solution of mono-adduct 23 which was evaporated to remove the hexane and then diluted with toluene to a total volume of 500 mL. The resulting solution was deoxygenated by purging with Ar for 10 min, further degassed by two freeze-pump-thaw cycles and then heated under Ar to 80 "C for 44 h. After concentration to 100 mL, the orange-red solution was chromatographed under exclusion of air and light (SiO,, PhMe/hexane 2 : 1) to afford one main product which was recrystallized from CS2/MeOH then from CSz/hexane and dried to give 24 (27.7 mg, 23%) as a black solid. M.p. > 270 "C.

7.5.3 Preparation of Tris-adduct28 by Addition of the Anchor-Tether-Reactive-group Conjugate 27 to C60 (Scheme 7-4) [47] To a solution of C,,) (2.753 g, 3.82 mmol) and 27 ( 1 .O g, 1.91 mmol) in toluene (700 mL), DBU (320 mg, 2.10 mmol) in toluene (50 mL) was added over 5 min. Afier 3 h, the mixture was concentrated to 100 mL, diluted with hexane (100 mL). and chromatographed (SO,, toluene/hexane I : 1 then 2 : 1) to give the wine-red monomethanofullerene. After evaporation of hexane, toluene was added to give a total volume of 2.5 L, then the solution was deoxygenated by purging with Ar for 1.5 h and heated to reflux for 36 h. Concentration and column chromatography (SiO,, toluene), followed by recrystallization from CHCIJMeOH and drying gave 28 ( I .335 g, 60%) as a brown solid. M.p. > 270 "C.

7.5.4 Formation of Tetrakis-adduct 20 by Removal of the Tether in Hexakis-adduct 30 and Transesterification (Scheme 7-5) [2] A solution of 30 (200 mg, 0.122 mmol) and C6()(102 mg, 0.142 mmoL) in chlorobenzene (160 mL) was irradiated in a Pyrex photochemical reactor at 20 "C for 2 h with a medium-pressure Hg lamp, while a stream of 0, was bubbled through. The mixture containing 31 (R, = 0.43, TLC, S O 2 , CH,Cl,/AcOEt 9 : 1) was then transferred into a flask and deoxygenated by inserting a stream of Ar, and PPh, (320 mg, 1.221 mmol) in chlorobenzene (5 mL) was added. After stirring at 20°C for 1 h under Ar, plug filtration (SiO,) with toluene to remove chlorobenzene and C,,, then with CH,CI,/AcOEt 19: I and then 9 : 1, yielded 32 which was precipitated out of CH,Cl, by addition of hexanc: 183 mg (90%). TsOH (54 mg, 0.1285 mmol) and DMAD (135 mg, 0.950 mmol) were added to a solution of the isomeric mixture 32 (159 mg, 0.095 mmol) in deoxygenated toluene (200 mL), and the mixture was refluxed for 4.5 h in the dark. Column chromatography ( S O , , CH,Cl, followed by CH2C12/AcOEt49 : 1 then 24 : 1) yielded 33 as a yellow-green product, that was precipitated from CH,Cl, by addition of hexane: 86 mg (47%) of a bronze solid. To a solution of 33 (30 mg, 0.0156mmol) in anhydrous EtOH/THF 1 : 1 (30 mL) was added K2C03(155 mg, 1.123 mmol), and the mixture was stirred at 20 "C under Ar for 3.5 h. After filtration and evaporation, column chromatography (SiO,, CH,CI,/AcOEt) afforded 20 which was precipitated from CH,CI, by addition of hexane: 17 mg (80%) of a bronze solid. M.p. > 270°C.

7.5.5 Binge1 Macrocyclization: Synthesis of cis-2 Bis-adduct 42 Starting from Benzene-1,2-dimethanol(Scheme 7-8) [25] Ethyl 3-chloro-3-oxopropanoate(ethyl malonyl chloride, 2.3 mL, 18.09 mmol) was added to a stirred solution of benzene-1,2-dimethanol (1.00 g, 7.24 mmol) and pyridine (1.5 mL, 18.09 mmol) in CH,Cl, (100 mL) at 0°C. The solution was allowed to slowly

214

7 Regio- and Stereoselective Multiple Functionalization of Fullerenes

warm to 20 "C (over 1 h) and then stirred for 3 h. The mixture was washed with saturated aqueous NH4CI solution (2x), dried (MgSO,), and evaporated to dryness. Column chromatography (SO,, CH,CI2/MeOH 97 :3) yielded 1,2-bis{[(ethoxycarbonyl)acetoxylmethy1)benzene (1.8 1 g, 68%) as a colorless oil. DBU (0.4 mL, 2.496 mmol) was added at 20 "C to a solution of c6()(300 mg, 0.416 mmol), I, (21 1 mg, 0.832 mmol) and 1,2-bis{[(ethoxycarbonyl)acetoxy]methyl}benzene (152 mg, 0.416 mmol) in toluene (600 mL). The solution was stirred for 5 h. The crude material was filtered through a short plug (SO2) eluting first with toluene (to remove unreacted C6-,J and then with CH2C12. Column chromatography (SO,, CH,Cl,/hexane 2 : 1) and recrystallization (hexane/CHC13)provided 42 (151 mg, 33%) as a dark red solid.

7.5.6 Enantioselective Synthesis of cis-3 Bis-adduct ('C)-2 by Binge1 Macrocylization of (S,S)-66 with C, Followed by Transesterification (Scheme 7-11) 1251 DBU (0.25 mL, 1.662 mmol) was added at 20°C to c60 (200 mg, 0.277 mmol), I, (1 55 mg, 0.609 mmol), and (-)-(4$,5S)-bis { [(ethoxycarbonyl)acetoxyJmethyl}-2,2-dimethyl-l,3-dioxolane (S,S)-65 (119 mg, 1.662 mmol) in toluene (400 mL), and the mixture was stirred for 8 h. The crude material was filtered through a short plug (Si02), eluting first with toluene to remove unreacted C, and then with CH,CI,/MeOH 97 :3. Column chromatography (SO2) eluting with CH,Cl,/hexane 9 :1 yielded the corresponding cis-2 bis-adduct which was precipitated from CHClJhexane (61 mg, 20%), and eluting with CH,Cl,/MeOH gave cis-3 bis-adduct (S,S,'C)-66 which was precipitated from CH,Cl,/hexane (41 mg, 13%) to give a brown solid. K2C03(260 mg, 1.886 mmol) was added to (S,S,fC)-66(21 mg, 0.019 mmol) in THF/EtOH 1 : 1 (28 mL), and the mixture was stirred at 20 "C for 1.5 h, then filtered and evaporated to dryness. Column chromatography (Si02, toluene) followed by precipitation from CH,Cl,/hexane yielded (fC)-2 (8 mg, 40%) as a brown solid. M.p. > 250 "C.

Acknowledgment We thank the Swiss National Science foundation for continuing generous support of fullerene research and Prof. Jules Rebek, Jr., at the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, for hosting ED. for his sabbatical, during which this article was written.

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[68] J.-P. Bourgeois, F. Diederich, L. Echegoyen, J.-F. Nierengarten, Helv.Chim. Actu 1998. X I , 1835-1844. 1691 R. W. Alder, S. P. East, Chem. Rev. 1996,96,2097-2111. 1701 F. Cardullo, F. Diederich, L. Echegoyen, T. Habicher, N. Jayaraman, R. M. Leblanc, J. F. Stoddart, S . Wang, Langmuir 1998, 14, 1955- 1959. [7 I ] J.-F. Nierengarten, C. Schall, J.-F. Nicoud, B. Heinrich, D. Guillon, Tetrahedron Letr. 1998, 39,5747-5750. [72] J.-F. Nierengarten, D. Felder, J.-F. Nicoud, Tetrahedron Lett. 1999,40,269-272. [73] J.-F. Nierengarten, D. Felder, J.-F. Nicoud, Tetrahedron Lett. 1999,40,273-276. [74] J.-F. Nierengarten, L. Oswald, J.-F. Nicoud, Chem. Commun. 1998, 1545- 1546. [75] J.-F. Nierengarten, C. Schall. J.-F. Nicoud, Angew. Chem. 1998, 110, 2037-2040; Angew. Chem., Int. Ed. Engl. 1998,37, 1934-1936. [76] (a) J.-F. Nierengarten, D. Felder, J.-F. Nicoud, Tetmhedron Lett. 1998, 3Y, 2747-2750; (b)A. Soi,A. Hirsch, New. J. Chem. 1998, 1337-1339. 1771 J. M. Hawkins,A. Meyer, M. Nambu, J . Am. Chem. Soc. 1993,115,9844-9845. [78] R. Kessinger, J. Crassous, A. Herrmann, M. Ruttimann, L. Echegoyen, F. Diederich, Angew. Chem. 1998,110,2022-2025;Angew. Chem., Int. Ed. Engl. 1998,37, 1919-1922. [79] A. Herrmann, F. Diederich, Helv. Chim. Actu 1996, 79, 1741 - 1756. [80] D. Philp, J. F. Stoddart, Angew. Chem. 1996,108,1242-1286; Angew. Chem., Int. Ed. EngI. 1996,35, 1154- 1 1 96. [81] M. Kawaguchi, A. Ikeda, S. Shinkai, J. Chem. Soc., Perkin Truns. I 1998, 179-184. [82] P. S. Baran, R. R. Monaco, A. U. Kahn, D. I. Schuster, S. R. Wilson, J. Am. Chem. Soc. 1997,119,8363-8364. [83] F. Arias, L. A. Godinez, S. R. Wilson, A. E. Kaifer, L. Echegoyen, J. Am. Chem. Soc. 1996, 118,6086-6087. [84] D. A. Leigh, A. E. Moody, F. A. Wade, T. A. King, D. West, G. S. Bahra, Langmuir 1995, 11,2334-2336. [85] U. Jonas, F. Cardullo, P. Belik, F. Diederich, A. Giigel, E. Harth, A. Herrmann, L. Isaacs, K. Miillen, H. Ringsdorf, C. Thilgen, P. Uhlmann, A. Vasella, C. A. A. Waldraff, M. Walter, Chem. Eur: J. 1995, I , 243-251. [86] J. Osterodt, M. Nieger, P.-M. Windscheif, F. Vogtle, Chem. Ber: 1993, 126,2331-2336. [87] H. Imahori, K. Yamada, M. Hasegawa, S. Taniguchi, T. Okada, Y. Sakata, Angew. Chem. 1997,109,2740-2742; Angew. Chem., Int. Ed. Engl. 1997,36,2626-2629. [88] D. Carbonera, M. Di Valentin, C. Corvaja, G. Agostini, C. Giacometti, P. A. Liddell, D. Kuciauskas, A. L. Moore, T. A. Moore, D. Gust, J. Am. Chem. Soc. 1998, 120, 43984405. [89] Y. Rubin, S. Khan, D. I. Freedberg, C. Yeretzian, J. Am. Chem. Soc. 1993,115, 344-345. [90] P. Belik, A. Giigel, J. Spickermann, K. Mullen, Angew. Chem. 1993, 105, 95-97; Angew. Chem., Int. Ed. Engl. 1993,32, 78-80. [91] (a) Y. Rubin, Chem. Eul: J. 1997, 3, 1009-1016. (b) W. Qian, Y. Rubin, Angew. Chem. 1999,111,2504-2508; Angew. Chem. Int. Ed. 1999,38,2356-2360. [92] M.-J. Arce, A. L. Viado, Y.-Z. An, S. I. Khan, Y. Rubin, J. Am. Chem. Soc. 1996, 118, 3775 - 3776. [93] M. Taki, S. Sugita, Y. Nakamura, E. Kasashima, E. Yashima, Y. Okamoto, J. Nishimura, . I . Am. Chem. Soc. 1997,119,926-932. [94] M. Taki, Y. Nakamura, H. Uehara, M. Sato, J. Nishimura, Enuntiomer 1998, 3, 231 -239. [95] T. Ishi-i, K. Nakashima, S. Shinkai, Chem. Commun. 1998, 1047-1048. [96] T. Ishi-i, K. Nakashima, S. Shinkai, K. Araki, Tetrahedron 1998,54, 8679-8686.

218

7 Renio- and Stereoselective Multiple Functionalization of Fullerenes

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[98] E. Nakamura, H. Isobe, H. Tokuyama, M. Sawamura, Chem. Commun. 1996, 1747- 1748. [99] H. Isobe, H. Tokuyama, M. Sawamura, E. Nakamura, J. Org. Chem. 1997,62,5034-5041. [loo] M. Prato, Q. C. Li, F. Wudl, V. Lucchini, J . Am. Chem. SOC. 1993, 115, 1148-1150. [loll A. Hirsch, Principles ojFu1lerene Reactivity, in [6], pp. 1-65. [I021 L.-L. Shiu, K.-M. Chien, T.-Y. Liu, T.-I. Lin, G.-R. Her, T.-Y. Luh, J. Chem. SOC.,Chem. Commun. 1995, 1 1 59- 1160. [103] C. K.-F. Shen, K.-M. Chien, C.-G. Juo, G.-R. Her, T.-Y. Luh, J. Org. Chem. 1996, 61, 9242- 9244. [ 1041 C. K.-F. Shen, H.-h. Yu, C.-G. Juo, K.-M. Chien, C.-R. Her, T.-Y. Luh, Chem. Eur: J. 1997, 3,744-748. [lo51 For a possible mechanism, see: E. U. Wallenborn, R. F. Haldimann, F.-G. Klarner, F. Diederich, Chem. Eur: J. 1998,4,2258-2265.

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

8 Template Controlled Oligomerizations Ken S. Feldman, Ned A. Porter, Jennifer R. Allen 8.1 Introduction The synthesis of repeating molecular units with control of stereochemistry has been the subject of much research in the natural products arena, and significant advances have emerged from both traditional ionic chemistry and free-radical chemistry [ 11. For example, (-)-lardohre (l),the aggression pheromone of Lardoglyphus konoi, contains four identical units, as emphasized by the abbreviated and equivalent representation l', Scheme 8-1. Both enantiomers of lardolure have been synthesized using a linear approach by the groups of Mori and Yamamoto [2,3]. In addition, controlled-length oligomers can be found within the backbone of the polyene macrolide antibiotics, naturally occurring 1,3-p0lyols that constitute an important class of clinically valuable antifungal agents. A recent synthesis of filipin Ill (2) exemplifies the stepwise, iterative approach that defines current art in the construction of targets containing these repeating molecular segments [4].

QH _ OH - 9_H O _H O H_ 9H_

HO 1 (-)-lardolure

1'

2 filipin Ill

Scheme 8-1 Representative oligomeric natural products.

An attractive and powerful feature of free-radical addition sequences is their ability to create multiple carbon-carbon bonds in a single reaction [ 5 ] . In order for this methodology to be successful in the synthesis of repetitive molecular fragments such as those noted above, two general considerations must be addressed: (1) control of stereochemistry, and (2) control of the number of iterative units which become incorporated. There has been intense interest in the control of stereochemistry of free-radical addition reactions by use of chiral auxiliaries [6] and, even more recently, using enantioselective catalysis [7- 121. As a result, the current understanding of stereochemical control has clearly progressed to the point where this obstacle can be overcome. There have also been reports of strategies that simplify telomer distribution in free-radical oligomeriza-

220

8 Temulute Controlled Oligomerizations

tions [ 131. While simple adjustment of the monomerkhain transfer reagent ratio can provide a crude measure of dispersity control, this approach is only satisfactory for the lowest telomers. Two distinct but related strategies that rely on templates to control the number of monomers incorporated into an oligomeric product can be envisioned. One of these approaches, shown in Scheme 8-2, relies on templated radical macrocyclization reactions to control telomer size [14, 151. This strategy requires attachment of all of the monomer units to the template backbone and uses macrocyclization, which faces competition from intermolecular chain transfer, to control the telomer length. The chain transfer agent T-I' (i.e., telomerization terminator) is not attached to the template.

4

4

3

I

5

6

T

Scheme 8-2 Oligomerization control via template-bound monomers. I' = radical initiator,T- I' = chain transfer agent.

The second approach, shown in Scheme 8-3, relies on attachment of both the radical initiating and radical terminating functionalities, but none of the monomer units, onto a rigid backbone [ 16- 181. Upon initiation, intermolecular chain growth proceeds until the growing telomer spans the length of the template backbone and intramolecular termination (macrocyclization) becomes feasible. Thus, the distance between the initiating end and the terminating end defines the number of monomer addition steps that can occur before termination.

7

8

9

10

Scheme 8-3 Oligomerization control via template-bound initiator and terminator. I = radical initiator, T = radical terminator.

8.2 Controlled Oligomerizutions with Tethered Morzotnrt~

22 I

8.2 Controlled Oligomerizations with Tethered Monomers One approach to oligomer control in a free-radical polymerization utilizes bound monomers and relies on templated radical macrocyclization reactions. Successful execution of this strategy requires that cyclotelomerization effectively compete with intermolecular chain transfer. Scheme 8-2 in Section 8.1 depicts this chemistry schematically wherein radical addition (A), cyclization (C), and chain transfer (T) provide an n=3 telomer. The key macrocyclizations (cyclotelomerizations) must precede chain transfer. These transformations are well precedented by systematic investigations of free-radical macrocyclizations that appeared in the 1980s [ 19-23] and by the seminal contributions of Kammerer, Scheme 8-4 [24-341.

N

n

XLNWC

AIBN

n

12

13

Scheme 8-4 Kammerer’s strategy for template control of acrylate oligomerization.

8.2.1 Templates for n = 2 Telomers An investigation into the preparation of n = 2 telomers was successful in showing that the ACT strategy with templates of type 14 is a viable means for producing isotactic 1,3 stereocenters as exemplified in the production of 16 (n=2) (Scheme 8-5). The oxazolidine unit has documented success as a stereocontrol element in acyclic radical reactions [35-371, and thus its incorporation into this template provides, in effect, a chiral auxiliary to control the configuration of new stereogenic centers formed in the sequence. Exposure of 14 ( m = 3 , R = tert-Bu) to cyclohexyl iodide, allyltributylstannane, and AIBN leads to a macrocycle 15 with two new stereogenic centers. The ally1 group provides additional functionality for further transformations and also creates a new stereocenter in the process. In order to effect the desired macrocyclization, addition of the firstformed radical to the proximal acrylamide moiety must be faster than addition to the chain transfer agent allyltributylstannane, a requirement that can be fulfilled under appropriate reaction conditions. Premature chain transfer in this particular system, under conditions that discourage bimolecular reaction between two templates, leads to two simple n = 1 products (vide infra).

222

8 Temvlate Controlled Oliaomerizations

C6H,,$

16n=2

Scheme 8-5 The ACT reaction with templates of type 14 leading to n=2 telomers.

The combination of components within the covalent template assembly 14 that gave the best overall performance was identified through systematic variation in the length of the tether separating the template from the monomer, the configuration at the site of the auxiliary attachment, the auxiliary blocking group R, and the rigid base compound. It was found that each of these variables had a profound influence on the performance of the template assembly in obtaining n = 2 telomers 16. Impressively, in these studies 16 (n= 2) could be obtained as 87% of all of the telomers formed with a diastereoselectivity as high as 20 : 1. The telomer distribution histogram for reaction of 14 (m= 3, R = tertBu) is shown in Scheme 8-6.

looJ

R=H R = allyl

80 -

-c5

L.

b

€9

60-

GOOMe

40-

n

R 16 R= allyl 17 R=H

20 -

0 4

1

2

3

4

5

6

Telomer number, n Scheme 8-6 Telomer distribution for reaction of template 14 (m= 3, R = terr-Bu) with allyltributylstannane and cyclohexyl iodide.

8.2 Controlled Ohomerizations with Tethered Monomers

223

8.2.2 Templates for n = 4 Telomers It is of some interest to inquire if this template strategy can be applied to the construction of telomers with n > 2 . This point is of some practical importance since the smaller oligomer units can be approached by efficient synthetic sequences that do not rely on templated chemistry. As the telomer length increases, non-template strategies become tedious and time-consuming, while the template approaches may provide a more direct route to oligomers of defined length. A strategy for achieving n = 4 telomers is shown in Scheme 8-7. A template that has four attached monomers can serve, via intramolecular macrocyclizations, to control the telomer length. After addition of an initiating radical to one of the monomers, three consecutive macrocyclizations followed by chain transfer would yield the desired n = 4 polycycle 21. Any deviation from the sequence (e. g., three consecutive cyclizations followed by chain transfer) would not lead to the desired n = 4 telomers. Competing processes that are available include failure to cyclize prior to chain transfer, intramolecular chain transfer by a hydrogen atom abstraction process, or intermolecular addition reactions of templates. It is recognized that the last deviation gives rise to the possibility of obtaining telomers higher than n=4, while premature chain transfer gives telomers smaller than n =4.

18

21

19

I

20

Scheme 8-7 An approach to n =4 telomers with control of stereochemistry.

In analogy to the n = 2 template 14, template 24 was prepared according to Scheme 8-X. This compound was prone to light initiated polymerization when left concentrated and therefore was stored as a stock solution typically on the order of 1 .O M in benzene. The n = 4 base was synthesized starting from protocatechuic acid. Bis-ester formation was

8 Template Controlled Olinomerizations

224

achieved by protection of the phenolic functionalities (TBDMS) followed by conversion of the free acid to the corresponding acid chloride [38] and coupling with ethylene glycol. Deprotection of all four silyl ethers with HF gave the tetraphenol 22. Tetraetherification of this tetraphenol with an excess of the known oxazolidine acrylamide 23 gave 24 in 45% yield.

I

OH

22

OH

+

23 24

Schemes-S Synthesis of the n = 4 template 24. Key: (a) K,CO,, catalytic [18]crown-6, 30% DMSO, acetone, reflux, 18 h.

The ACT sequence with template 24 was expected to give a complex mixture of products. Success in obtaining n = 4 telomers by this sequence is obviously dependent on the balance between the rate of chain transfer, the rate of cyclization, and the rate of intermolecular addition. Formation of the n = 4 product requires three consecutive macrocyclizations prior to chain transfer. If the rate of chain transfer is too high, premature quenching of intermediate radicals will lead ultimately to smaller telomers. It is clear that cyclization can be promoted, in part, by lowering the concentrations of allyltin (Sn) and template (T), provided that intermolecular reactions remained suppressed. For analysis, the crude ACT reaction mixtures were subjected to a standard telomer assay as follows [14, 151. The tin products were removed by chromatography and treatment with KF. The resulting macrocyclic mixtures were then hydrolyzed under acidic conditions to yield the corresponding acrylic acid telomers. Hydrolysis of the desired n = 4 macrocycle is shown in Scheme 8-9. Esterification of the reaction mixture with diazomethane gave the methyl acrylate telomers 26 that were then readily identified by gas chromatography/mass spectrometry. A simple template-free methyl acrylate telomerization was conducted using the cyclohexyl iodide/allyltributyltin system in order to identify retention times for the telomers 26 from the ACT reactions. Telomerization of methyl acrylate (900 mM) with 120 mM cyclohexyl iodide and 300 m~ allyltributyltin gave 27% of the n = 4 telomers, Scheme 8-10. Under the best GC conditions found, only four different n =4 telomers, out of a possible 16, were observed in this product mixture. This experiment gives a baseline value for telomer distribution obtained without the use of a template. It is clear that simple templatefree telomerization is not useful for the preparation of an oligomer of a specific length.

8.2 Controlled Olipomerizations with Tethered Monomers

225

25b R' =Me

21

Scheme 8-9 Assay procedures for analysis of ACT reactions giving n = 4 products. 100-

80 e S n B u 3

60 40

@COOMe

-

C6Hlll __c

Benzene

c6H1

AlBN

80

"C

26

20 n "

1

2

3

4

5

Telorner number, n

6

Sc..eme 8-10 Histogram for template-free methyl acry .-te telomerization with 900MA/120'/3OOs".

The reagent ratios chosen for initial studies with template 24 were based on previous work on the templated ACT reaction: 2.5 mM in 24, 80.0 mM in cyclohexyl iodide (I), and 200.0 mM in allyltin (abbreviated from this point forward as 2.5T/801/200s"). The product histogram acquired for this reaction, following the standard telomer assay, is shown in Scheme 8-11a. The results obtained were promising in some aspects. First, the desired n = 4 product was the major telomer formed, at 35%. Secondly, only two n = 4 isomers in a ratio of 8.5: 1 were detected by GC analysis. For comparison, the n = 2 isomers that are easily separated were found in a ratio of 17 :1. Lastly, no telomers 26 higher than n = 4 were detected, an observation consistent with suppression of bimolecular reactions. Based on these results, ACT with 24 was investigated under conditions with lower ratios of both templatehitiator and chain transfer agenthitiator. The results obtained from ACT under 1.OT/80'/1OOs" conditions are shown in Scheme 8- 1 1 b. In contrast to the product distribution obtained under the conditions described in Scheme 8- 1 1 a, more of the longer telomers is formed at the expense of the shorter ones. In addition, 50% of all of the telomers formed had n=4. Under these conditions, four n = 4 stereo-

8 Terndute Controlled Olixomerizations

226

isomers were detected by GC analysis in a ratio of 1 .O : 2.1 : 21.9 : I .O. One complication in this reaction, however, was the production of telomers that were terminated by hydrogen atom abstraction instead of by addition to the chain transfer agent allyltributylstannane. These products are shown in the product histograms as the darker portions in the stacked columns and, in this reaction, make up 10%of the total oligomers formed. The formation of these H-terminated species was also seen in the previous studies with template 14 and presumably results from an intramolecular process [39]. a.

b.

100

100 80

80

-5 L

..-. 0 a.l

e

60

5

e,

40

0

#

20 0

1

2

3

4

5

Telomer number, n

6

6o 40 20 0

1

2

3

4

5

6

Telomer number, n

Scheme 8-11 Product histogram for ACT of 24 under (a) 2.5T/80'/200S"; (b) 1.0T/80'/100S" conditions.

A further attempt was made to optimize tetramerization with this template system. However, the results for the ACT of 24 with a 2.5T/801/100s"ratio of components were rather disappointing. The major telomer formed under these conditions was the n = 3 species and not the desired n = 4 oligomer. In addition, a small amount of the higher n = 5 and 6 telomers were seen in these experiments, but no products resulting from hydrogen atom abstraction were detected. Clearly, adjusting the chain transfer agent's concentration to maximize cyclotelomerization and minimize side reactions is difficult with this system. The feasibility and practicality of the ACT sequence in obtaining diastereomerically pure n = 4 telomers were investigated using the optimum conditions determined for template 24. The possibility of isolation of the desired n = 4 template from all of the other reaction products by the use of HPLC was explored. In a standard template-free stereorandom methyl acrylate telomerization, three peaks are observed for the n = 3 telomers by normal-phase HPLC and three more broad peaks are separated for the n =4 telomers. Each of these latter peaks represents a mixture of isomers as determined by GC analysis. An ACT reaction with 225 mg of 24 under 1.0T/80'/100s"conditions was performed, the resulting mixture was subjected to the telomer assay procedure, and the oligomeric products were then purified by HPLC (Scheme 8-12). Only one peak was observed for the n = 3 and n = 4 telomers, although the n = 4 peak exhibited a slight shoulder. Gas

8.2 Controlled Oligomerizations with Tethered Monomers

227

chromatography, high-resolution mass spectrometry and two-dimensional 'H-NMR spectroscopy all revealed that the compound isolated, 27, was a single n = 4 diastereomer. HETCOR analysis showed this compound to be all isotactic, as described below and shown in 27. The isolated 10 mg of 27 represents a 20% overall yield starting from 24. In addition, 6 mg of an all-isotactic n = 3 telomer was isolated,

AlBN

80 "C

100°C

27

20%

Scheme 8-12 ACT reaction maximizing formation of the n = 4 isotactic telomer.

Much literature precedent supports the assignment of tacticity in methyl acrylate polymers using NMR techniques [40,41]. In the 'H-NMR spectrum, the shift of the methylene protons is sensitive to dyad stereochemistry. For example, in an isotactic (meso) dyad 28, the methylene protons are chemically non-equivalent and appear as two separate sets of signals, whereas in a syndiotactic (racemic) dyad 29, the methylene protons are equivalent. The 'H-NMR spectrum of 27 showed multiplets at 1.89 and 1.5 ppm due to the two diastereotopic methylene protons of the isotactic dyad. The rest of the spectrum is consistent with the structure of the n = 4 tetrad 27. A racemic dyad structure would have been expected to give resonances of intermediate shift to that of the two resonances observed for the telomer 27. This evidence strongly implies that 27 has the allisotactic configuration shown in Scheme 8-12. Two-dimensional techniques (HETCOR) also give information about triad and tetrad configuration [42]. The 'H multiplets at 1.89 and 1.5 ppm couple to three secondary carbon atoms at 34.94,34.23, and 33.42 pprn in the I3C spectrum. These methylene carbons do not show crosspeaks with any other region in the proton spectra. Thus, these results show that the major isomer isolated from the ACT reaction of 24 is all isotactic. Although this characterization does not allow determination of the absolute stereochemistry of 27, the tentative assignment shown is consistent with expectations based upon previous work done with chiral oxazolidine auxiliaries. The results presented herein show that the ACT strategy to obtain higher telomers has some promise. ACT sequences with templates designed to obtain n = 4 telomers have been successful, as the desired product is isolated from these reactions in 20% overall

228

8 Template Controlled Oligomerizations

yield. It is clear, however, from the concentration studies that optimization of this system is complex, most expectedly because of the requirement for three consecutive macrocyclizations. Making these macrocyclizations more efficient would offer a potential solution and could make the ACT sequence more useful.

8.2.3 Ether-based Templates Templates based on ether tethers also have been examined. Improvements in product yield may be anticipated from the reduced steric congestion in the cyclization step due to the substitution of an -0 linkage for a -CH, linkage [43]. In addition, such oxygenated tethers might serve as crown-ether type substrates, sequestering ions that in turn serve to promote macrocyclization. The beneficial effect on macrocyclization rates by complexation of this type has precedent in the work of Mandolini and Illuminati [44]. The synthesis of the requisite glycol tethers is shown in Scheme 8-13 and starts from diethylene glycol (30). Hydroxyl monoprotection within 30 as a tert-butyldimethylsilyl ether was followed by oxidation of the remaining OH unit to give the corresponding aldehyde 31. This oxidation reaction was very problematic in that all other oxidants examined gave the ester corresponding to oxidation of the hemiacetal product resulting from starting alcohol attack on product aldehyde. The Dess-Martin reagent [45-471, however, was outstanding in obtaining 31 without the formation of side products. Reaction of 31 with methylmagnesium bromide gave the carbinol, and subsequent oxidation with PCC gave the ketone 32. This ketone was converted to the requisite oxazolidine acrylamides 33 and 34 by the same procedure as was utilized in the synthesis of 14. These diastereomeric species were easily separable using flash column chromatography. The first-eluting tethers typically have the methyl and auxiliary anti to one another whereas the second eluting isomer has the alternative syn arrangement.

31

30

'

34 R=TBDMS 36R=H 38 R=Tos RO

c

32 R=TBDMS

c RO

'c

33 R=TBDMS 35R=H 37R=Tos

Scheme 8-13 Synthesis of ether-based tethers. Key: (a) TBDMS-Cl, imidazole, DMF, 93%; (b) Dess-Martin reagent, CH,C12, 100%; (c) MeMgBr, Et20,0 "C, 81%; (d) PCC, CH,C12, mol sieves, 90%;(e) S-valinol, benzene, cat. TsOH, 80 "C then acryloyl chloride, Et3N,cat. DMAP, 69% combined; (f) Bu,NF, THF, OOC, 100%; (g) TsCl, pyridine, CH,C12, 85%.

8.2 Controlled Oligomerizations with Tethered Monomers

229

The corresponding n =4 polyether template 40 was synthesized according to Scheme 8- 14. Coupling of the methyl ester of protocatechuic acid (39) with two equivalents of the diastereomerically pure tosylate 38 gave 40 in 83% yield.

30% DMSO acetone reflux

38

39

Scheme 8-14 Preparation of template 40 with ether-based tethers.

It should be noted that the ACT sequence and the standard telomer assay were employed to study oligoselectivity with this template and thus the products analyzed are the same methyl acrylate telomers identified in the previous studies. The ACT reaction of 40 under standard conditions with cyclohexyl iodide and allyltributyltin (2ST/80'/2OOs"), without the aid of a counter-ion, showed interesting results. The product histogram obtained with 40 after telomer assay is presented in Scheme 8-15. 100

B

-E

80 60

u0

-& 40 20 0

1

2

3

4

5

Telomer number, n

6

Scheme 8-15 Product histogram for ACT of 40 under 2.5T/801/200s"conditions.

Although 96% of the telomers formed were the desired n = 2 species, a significant amount (30%) were terminated by hydrogen atom abstraction to give 42 rather than by reaction with allyltributyltin to furnish 16 (n= 2) (Scheme 8-16). While intervention of this competing chain transfer process has been seen in previous work (vide supra), in this sequence it appears to be extreme. Modifying the tethers to include an oxygen atom apparently promotes a more facile intramolecular hydrogen atom abstraction.

230

8 Template Controlled Oligomerizations

42

Scheme 8-16 Proposed H-atom abstraction in the chain transfer sequence.

A possible source of the abstracted hydrogen atom is indicated in Scheme 8- 16 [48]. A 1,%abstraction as shown is analogous to “back-biting” reactions found in polymer chemistry and therefore it would not be surprising if these abstractions were operating in the ACT reaction. Chain transfer of the intermediate carbon radical in 41 to the methylene adjacent to the tether oxygen would continue the chain, and work-up would lead to product 42. The hydrogen atom source has not, however, been unambiguously identified. As a first impression, these results were somewhat promising because they showed that replacing a carbon atom with an oxygen atom in the tether did enhance the macrocyclization. For example, in the analogous five-atom system with carbon (e.g., 14, m = 3, R = tert-Bu), the same conditions resulted in 80.5% of the n = 2 telomer compared to 95% in the system with the glycol tethers. This enhancement is not surprising because of the reduced transannular interactions in the glycol system. The drawback in this system remains, however, the significant amount of hydrogen atom abstraction rather than chain transfer (30%). Complexing an appropriate ion within the macrocycle might alter these product ratios. Telomerizations carried out in the presence of potassium tetraphenylborate and other tetraarylborate salts did not result in any change in the product histograms, nor were any changes observed in the ‘H-NMR spectrum of the starting template 40, even at high temperatures. A systematic investigation of these templates with a variety of Lewis acids may lead to an appropriate system for this free-radical transformation. This work remains for the future.

8.3 Controlled Oligomerizations with a Polynorbornane-based Template The template approach to controlling oligomerization described in the preceding section requires prior attachment of the monomer units to a (semi-)rigid backbone. An alternative strategy relies on template-bound initiating and terminating functionalities that spatially define the reactivity loci for simple unattached monomers (Scheme 8-3). Upon initiation, intermolecular chain-growth polymerization proceeds until the growing telomer bridges the template backbone and intramolecular termination via macrocycliza-

8.3 Controlled Oligomrrizations with a Polynorbornane-based Template

23 1

tion becomes feasible. Thus, the size of the template-bound oligorner produced by this sequence should, in principle, correlate with the size of the initiator-terminator gap of the template. This approach to oligoselective polymerization is described in this section.

8.3.1 Template Design and Synthesis The synthesis of rigid rod templates with the general structure 7 is predicated upon two key observations: (1) Norbornadiene (NBD, 43) can be polymerized under nickel(0) catalysis to give predominantly trans-anti-trans disposed oligomers [49], and (2) norbornene is an effective dienophile in anthracene-based Diels-Alder reactions [50]. From this foundation, templates with appropriately positioned functionality featuring either 13, 17, or 24 A gaps spanning putative initiator and terminator units can be assembled. In each case, issues of stereoisomer separation and stereochemical assignment must be addressed before oligomerization studies start. In addition, reagent compatibility while selectively manipulating chemically disparate initiator and terminator moieties, and an overarching concern about solubility of intermediates and the final templates, all demand attention. The resolution of these issues en route to the preparation of a family of (NBD),-based templates of potential use for controlling oligomer length in polymerization reactions is described below. The nickel(0)-mediated polymerization of norbornadiene developed by Pruett and Rick at Union Carbide represents one of the simplest and most efficient protocols for accessing functionalized, rigid rod molecules of approximately nanometer length. This process could, in principle, provide a broad mixture of oligomeric polynorbornadiene products. However, concentratiordsolvent regimes can be identified under which a physical property, solubility, imposes a stop-message on the polymerization. Thus, reaction of a concentrated solution of norbornadiene in 1P-dioxane with 0.2 mol% of NiCOD, precatalyst leads to a solid residue from which the trans dimer 44, the trans-anti-trans trimer 45 and the trans-anti-trans-anti tetramer 46 can be isolated in pure form by sequential fractional sublimation and then recrystallization from isopropanol (i-prOH) (Scheme 8-17). The final recrystallization removes small amounts of diastereomeric oligomers. It is noteworthy that the dimer/trimer/tetramer suite of products accounts for 94% of the starting norbornadiene. NBD tetramer insolubility severely limits further reaction. Structurally similar rigid rod spacers have been prepared through an iterative linear synthesis by Warrener and Butler [51,521. These species are formed as single isomers by this stepwise approach without the need for a tedious separation, but at the cost of overall efficiency. For the planned oligomerization scouting studies, rapid access to

%by+*+/

0.2 mol % NiCOD2 43

44

57%

45

34%

Scheme 8-17 NiCOD,-catalyzed norbomadiene oligomerization.

/

46

3%

232

8 Temolate Controlled Oliromerizations

large amounts (> 1 g) of template was deemed essential, and so the Union Carbide group’s “shotgun” oligomerization approach was preferred. A high-lying HOMO for the strained alkene in norbornene and, presumably, the higher oligomers 44-46, makes it an attractive partner for an electron-deficient diene such as methyl 9-anthracenecarboxylate (47) (Scheme 8-18). High yields of a 1 : 1 stereoisomeric mixture of the double Diels-Alder cycloaddition products 48/49 and 50/51 emerged from combination of 45 and 46 with 47, respectively [ 171. In both cases, the diastereomeric products were separated cleanly by chromatography. The C, 48 and C, 49 (NBD), isomers could be distinguished by their characteristic ‘H-NMR signals (48: H,#H,, 6 1.73, 1.63; 49: Ha=&, 6 1.67). The (NBD), templates 50 and 51 were more difficult to differentiate, but eventual recourse to the derived Mosher esters 52 and 53, respectively, permitted unambiguous assignment. Thus, the diester 52 prepared from the C, symmetric diester 50 exists as two diastereomers that could be separated by HPLC, whereas its counterpart 53, derived from the Ci-symmetry diester 51, is a single compound that displays two distinct OCH3 signals.

45

48

47

49

170 OC

46

47

60%

Scheme 8-18 Template synthesis via double Diels- Alder cycloaddition of anthracene endcaps to norbornadiene oligomers.

8.3 Controlled Oligomerizations with a Polynorbomane-based Template

233

Access to an even longer template formally derived from an NBD hexameric spacer can be achieved via the mono Diels-Alder adduct 54 (Scheme 8- 19).This species, available through incomplete reaction of 45 with 47, can be photodimerized under the influence of (CuOTf), to furnish the (NBD),-containing templates 55/56 in modest yield as an inseparable mixture of diastereomers. No further studies were performed with this material, as a pure sample of the required C, isomer was not forthcoming.

(Cu0Tf)pPhH

hu

55 R = R 1 = COZCH~,R2 =H 56 R = A 2 = COZCH,, RT = H

15%

Scheme 8-19 Synthesis of an (NBD),-based template by photodimerization of a norbornene precursor.

The majority of the exploratory template functionalization reactions were pursued with the Cs-symmetric (NBD),-based template 48. A series of related templates designed to arrest free-radical alkene polymerization, 63-66, were prepared from diester 48 through straightforward chemistry (Scheme 8-20) [ 171. A trichloroacetyl initiator was chosen based on the documented utility of this species in methacrylate polymerizations, especially graft polymerizations [53].The choice of terminator moiety required some deliberation, given the absolutely critical role that this unit will play in stopping the polymerization. The methacrylate derivatives 63-66 were selected for two attributes that might predispose this template construct towards oligoselectivity: (1) They should be intrinsically more reactive to a methacryloyl radical than the monomer methacrylate, and (2) they feature an effective radical leaving group appropriately positioned to serve as a “stop-message’’upon radical addition to the alkene terminus. Similar functionalization chemistry with the (NBD),-derived diester 50 afforded the trichloroacetyl, phenylthiomethacrylate-bearingtemplate 67 whose initiator-terminator pair spans an approximately 17 A gap (Scheme 8-20). Single-crystal X-ray analysis of the phenylthio-containing species 63 provided a detailed glimpse of the fully functionalized template (63’, Scheme 8-20). The anthracene-derived endcaps appear bowed slightly away from the apical ex0 hydrogens of the proximal norbornane units, as predicted by the molecular mechanics-based structural model 63”. These distortions are unlikely to have any consequence for the planned chemistry. Template-imposed oligoselectivity in (anionic) group transfer polymerization was also of interest with this template system. A suitable initiator-terminator pair for effecting this chemistry was proposed to be the trimethylsilylacetate/fluoromethacrylatespecies shown in the (NBD),-derived template 69 (Scheme 8-21). Under fluoride catalysis,

234

8 Template Controlled Olinomerizations

48 PhSH, NaH * 59R=SPh 88% TolSOzNa 60 R=SOzTol

89%

-

PhSeH, NaH 70% 1) TolSOzNa

-

66 X = SnBu3 42%

61 R = SePh

2) BLI~S~H,AlBN

62 R = SnBua

1 ) LiAIH4

60%

2) BuLi, 57

50

3) PhSH. NaH

c13c

4) Cl3CCOCl. DMAP

X-Ray structure of 63’

molecular mechanics structure of 63”

Scheme 8-20 Synthesis of initiator- terminator functionalized templates for controlling the free radical polymerization of activated alkenes.

HO 14% 68

R

69 R = Si(CH3)3 70R=H

Scheme 8-21 Synthesis of an initiator-terminator functionalized template for controlling the group transfer polymerization of methacrylate.

8.3 Controlled Oligomerizations with a Polynorbornane-based Template

235

silylacetates have been reported to initiate the group transfer polymerization of methacrylates [54].Termination of the silicon transfer oligomerization was anticipated to result from living-end silyl ketene acetal addition to the template-bound fluoromethacrylate unit, leading to fluoride ejection. The construction of these initiator and terminator units followed the strategy described earlier and is detailed in Scheme 8-21.

8.3.2 Measuring the Initiator-Terminator Gap in Molecular Terms The measured span between initiator and terminator attachment points (e.g., 13 A with 48) does not accurately represent the distance that must be traversed by a growing polymer chain as it bridges the initiator-terminator gap. Both the conformational preferences and the steric demands of the growing substituted hydrocarbon chain will surely conspire to trace a non-least-motion path of substantially greater length. Thus, prediction of oligomer size for any given template will not be straightforward. One approach to empirically measuring the “molecular size” of the initiator-terminator span utilizes bis-lactonization reactions with the (NBD), template diol68. In this experiment, the diol68 is condensed with either the bis-acid chlorides 71-76 (DMAP catalysis) or with the corresponding bis-acids 77-82 (Steglich/Keck conditions [%I) to furnish bis-lactones 84 (Scheme 8-22). Assuming that the rate of initial ester formation (e.g., 83) is independent of the chain length n, the yields of bis-lactone 84 will scale with the rate of macrolacton-

68

+XOC-

(CHdn-

71 n = 7, X = CI 72 n = 8, X = CI 73 n = 9, X = CI 74 n = 10, X = CI 75 n = 11, X = CI 76 n = 12, X = CI

cox

77 n = 7, X = OH

-

78 n = 8, X = OH 79 n = 9,X = OH 80 n = 10, X = OH 81 n = 11, X = OH 82 n = 12, X = OH

--

I

+ 71 . 7 6 )

84

n

Scheme 8-22 Bis-lactonizationexperiments to “measure” the effective initiator-terminator gap in the (NBD),-derived template.

8 Template Controlled Oligonierizations

236

ization. In turn, this macrolactonization rate will be sensitive to the chain dynamics and chain length of each activated diacid. Thus, to a first approximation, the highest-yielding macrolactonization should reveal the optimal chain length for the corresponding alkene oligomerization process. The data are presented in Scheme 8-22. Under both sets of reaction conditions, a clear preference for macrocyclization when n = 9 is observed. This chain length translates into the expectation that three olefinic monomer units should optimally fit between the initiator and terminator units of templates 63-66.

8.3.3 Model Studies for Optimizing Terminator Performance Preliminary scouting experiments were conducted prior to actual oligomerization studies in order to explore the effect of the radical leaving group X (cf. 86-91) in the key coupling step (Scheme 8-23). The halogen-containing model terminators were not effective partners for a chloroacetate-derived radical. In contrast, all of the chalcogen-based terminators performed with acceptable efficiency. Examination of relative radical leaving group abilities [56] (Scheme 8-23) does not lend any support to hypotheses that attempt to correlate reaction efficiency with X’ departure rates. While these experiments permitted exclusion of halogen-based terminators from further consideration, at this juncture the basis for choosing between the chalcogen variants was not evident. A final model experiment (Scheme 8-23) revealed that the trichloroacetate template moiety 85 and the chalcogen-based terminator template 90 indeed serve as an effective initiator-terminator pair for the uncontrolled oligomerization of methyl methacrylate.

O<

CCI,

85

85

-

86 X = CI 87 X = Br 88 X = 89X = SPh 90 X = SOaTol 91 X=SePh

0% 0%

1 65

69% 50% 59%

110 7

51%

92

a, ,-‘

Scheme 8-23 Model experiments designed to test the effectiveness of various terminating functionalities in free-radical polymerizations.

237

8.3 Controlled Oligomerizations with a Polynorbornane-based Template

8.3.4 Template Controlled Oligomerization Studies These encouraging preliminary results prompted extensive optimization studies of the template controlled oligoselective free-radical polymerization of methyl methacrylate (MMA) using the family of templates 63-65 (Scheme 8-24) [ 161. Early experiments with the sulfonyl terminator system 64 led, for the first time, to isolation of small quantities of macrocyclized material 94 - template controlled oligomerization had been achieved! Initial explorations of the effect of concentration, reagent ratio, and temperature variations on product 94 yield for the sulfonyl-based system led to the following optimized parameters: a 10-fold excess of monomer MMA and a 1.2-fold excess of Mo(CO), over template in benzene (10 mM in template) at 150 "C.These optimized conditions resulted in isolation of ca. 16% of the desired MMA-trimer-bound template 94 along with 25% of recovered template 64 and an equal amount of uncontrolled oligomer. Solvent characteristics also play an important, if ill-defingd, role in maximizing the yield of macrocyclized material. Limited template solubility necessarily constrained the solvent choices, but successful template controlled oligomerization of MMA with template 64proceeded in benzene, ethyl acetate, and isopropanol. Benzene appeared to be the solvent of choice among these options. Further examination of the influence of leaving group X on controlled oligomer formation revealed a substantial improvement with the thiophenyl-based species 63, whereas the PhSe analogue 65 offered little advantage over the sulfonyl case. Lower temperatures and longer reaction times also contributed to improved yields of macrocyclized product, and eventually as much as 47% of the MMA trimer species 94 could be isolated when the reaction was run under optimized conditions. A brief look at the effect of solvent variation on macrocycle 94 yield with the

m 0

64 X = SO2Tol

63 X = SPh

benzene ethyl acetate i-prOH

% 94 (diast. ratio) 16 (33:27:18:13:8) 10 10

+

94

/

' 1

benzene 47 (53:19:9:8:5:5) /f ethyl acetate 36 methyl isobutyrate 33 (39:20:19:6:13:3)

I \

-

20 27 26 65 X = SePh

.

CH3CN benzene i-prOH

cia E

-

x

95

Scheme 8-24 Oligoselective free-radical polymerization of MMA with the (NBD),-derived template: effects of variation in solvent and radical leaving group.

238

8 Template Controlled Oligomerizations

superior thiophenyl-bearing template 63 provided results consistent with the earlier studies using 64. Careful examination of the cyclization mixtures did not afford any evidence for formation of macrocyclized material with other than three MMA monomers bridging the initiator-terminator gap. Inspection of this (MMA), linker segment reveals that the n = 9 prediction from the macrolactonization experiments was precisely borne out. The stereochemical outcome of this oligoselective polymerization is of some interest. In principle, eight stereoisomeric macrocycles 94 can be formed. However, HPLC analysis of the cyclized material revealed that only six of these possibilities are represented in the product mixture. In benzene as solvent, over half of the product mixture is a single stereoisomer, whereas in methyl isobutyrate as solvent the diastereomers are more evenly distributed. Preliminary attempts to ascertain the relative stereochemistry of the major isomer within 94 via DNOE NMR measurements did not allow unambiguous assignment. Without this structural information in hand, further speculation on the relationship between chain stereochemistry and cyclization efficiency within 99 (see Scheme 8-27) is not warranted. Nevertheless, there must be some influence, given the non-statistical distribution of isomers. In comparison, the 'H-NMR spectrum of the pMMA portion of uncontrolled oligomer 95 is superimposable with that of atactic (i.e., random stereochemistry) pMMA. Exploration of the template controlled free-radical oligomerization of other activated olefins began with standard monomers utilized in bulk polymer synthesis and the template 63. Vinyl acetate and acrylonitrile led only to uncontrolled polymerization, while vinylene carbonate did not react under the standard experimental conditions. More exotic monomers, such as vinyl trifluoroacetate and tert-butyl acrylate, were also unsuccessful. Only methyl acrylate polymerization was arrested by template 64 to provide the macrocyclized product 96 in modest yield as a mixture of five diastereomers (Scheme 8-25). Subsequent studies with the more effective thiophenyl-bearing template 63 at lower temperatures improved this yield to 35%. The diastereomer distribution was reminiscent of the methyl methacrylate-derived product, aIthough no stereochemical assignments were made in this case either. Attempts to extend the template mediated free-radical oligomerization of MMA to the longer (NBD),-derived template 67 did not afford unequivocal results (Scheme 8-26).

63

96

35% (55:15:14:11:7)

Scheme 8-25 Oligoselective free-radical polymerization of methyl acrylate with the (NBD),derived template 63.

8.3 Controlled Olinomerizations with a Polynorbornane-based Temulate

239

h

Scheme 8-26 Oligoselective free-radical polymerization of MMA with the (NBD),-derived template 67.

Treatment of template 67 with 10 equivalents of MMA and 1.2 equivalents of Mo(CO), in benzene at 70 "C furnished a 21% yield of material which appeared by 'H-NMR spectroscopy to consist of a mixture of diastereomeric template-bound MMA tetramers. Unfortunately, all attempts to confirm this molecular composition by mass spectral analysis were not fruitful. Finally, the ability of the silylacetate, fluoromethacrylate-bearingtemplate 69 to enforce oligoselectivity on the group transfer polymerization of MMA was examined. However, no fluoride-initiated polymerization conditions could be identified which led to template-bound oligomer. Typically, off-template initiation (F-+MMA?) furnished uncontrolled polymer. In these cases, the template 69 suffered simple desilylation to deliver the acetate 70. Perhaps a template-bound silyl ketene acetal initiator would have performed in a more desirable manner, but that species remained elusive.

8.3.5 Mechanistic Studies: Probing Bimolecular Termination and Solvent Effects The maximum yield of the MMA trimerization product 94 from template 63 was 47%. In addition to this macrocyclic product, ca. 10% of unreacted template was recovered. The fate of the remaining ca. 40% of the original template was of some concern. An additional 20-25% of the template appeared to have a pMMA chain extending by about nine monomer units, on average ('H-NMR integration), from the initiator, and an intact terminator (cf. 100).The terminal functionality on the pMMA chain could not be identified, but no evidence for termination by the phenylthiomethacrylate moiety of a second template (i.e., bimolecular termination) could be found. At present, candidates for this radical quenching species include C1 and PhS (from Ph2S2formed as the reaction progresses). Thus, the intervention of bimolecular termination as a significant yield-limiting process is called into question. This curious observation refocuses concerns about yield loss to a critical choice that a template-bound pMMA radical 99 faces: macrocyclization to afford the controlled-

240

8 Temdate Controlled Olipomerizations

length oligomer 94 vs. addition of a fourth monomer to lead ultimately to 100 (Scheme 8-27). Furthermore, the energetics of these diverse reaction channels seem to be influenced by some characteristic of the solvent, as the aromatic solvent benzene apparently differentially favors the former path over the latter one compared to other non-aromatic solvents. Additional insight into the role (or lack thereof) of bimolecular termination in limiting macrocycle yield, and also into the effect of solvent on the options available to radical 99,was sought through the series of terminator challenge experiments discussed below.

0

0

94

,o-* cici

E

y

o

SPh

100

Scheme 8-27 Presumed mechanistic course of the template mediated oligoselective polymerization of MMA.

Varying amounts of two competing terminators, the simple methyl ester 106 and the template model ester 107, were introduced into the standard MMA oligomerization experiment with template 63 (Scheme 8-28) [18]. Both of these exogenous terminators were of comparable intrinsic reactivity in combination with a simple methacryloyl radical, as seen by the model reaction 101 + (102 + 103) + 104 + 105 shown in Scheme 8-28. The yield of macrocycle 94 was monitored as a function of the amount of 106 or 107 added in both the optimum solvent benzene and, independently, in a solvent chosen to resemble the growing pMMA chain, methyl isobutyrate.

24 1

8.3 Controlled Oligomerizations with a Polynorbornane-based Template

101 (0.1 equiv)

102(1 equiv)

103 (1 equiv)

104 R = temDl.@

benzene methyl isobutyrate

1 1

j 0 5 R = CH3

:

:

1 1

Scheme 8-28 Terminator challenge experiments: relative reactivity of the two probes 106 and 107 (as modeled by 102 and 103), and presumed role as bimolecular terminators in a controlled oligomerization experiment.

These four experimentswere designed to test two related hypotheses: (1) in an actual template system, bimolecular termination is suppressed as a consequence of the demanding steric environment about the terminator moiety. Observation of greater macrocycle yield with the bulkier terminator 107 present compared with the smaller analogue 106 in either solvent, given that these species have equivalent intrinsic reactivity with a small radical, would support this premise. (2) More pronounced solvent - solute interactions in benzene as compared to non-aromatic solvents contribute to favoring intramolecular termination (+ 94) over bimolecular monomer addition (+100) for radical 99. Observation of relatively greater macrocycle yield as either terminator concentration is increased in benzene compared to the same reaction in methyl isobutyrate is consistent with this hypothesis. The results of these studies are presented in complementary graphical form in Schemes 8-29 and 8-30. Scheme 8-29 displays the consequences of increasing terminator concentration on macrocycle yield independently for each solvent. In both benzene and methyl isobutyrate, the yields of macrocycle 94 were greater when 107 was present compared with 106. Presumably, the bulkier model template terminator 107 is less effective than the smaller methyl ester analogue 106 at intercepting radical intermediates en route to 94. Given the intrinsic reactivity equivalency between these two species with an unencumbered radical (Scheme 8-28), it is reasonable to conclude that the bulk of the template-oligomer construct 99 and the bulk of the terminator moiety in 107 are responsible for the differential reactivity observed. The differences are not large in either solvent (- lo%),but they can contribute to the surprising lack of substantial bimolecular termination in the polymerizing system.

242

8 Temnlate Controlled Oliaomerizations

I00 T

F\

80

0

107

0

106

1

80->

0

107

'0

.-N rJ

60

8

a Yr-

'

40

20

I

I

I

2

I

I

I

3 4 5

I

I

I

I

I

6 7 8 91011

equiv terminator methyl isobutyrate solvent

equiv terminator benzene solvent

Scheme 8-29 Template macrocycle 94 yield as a function of added terminator 106 or 107 in benzene and, independently, in methyl isobutyrate solvent.

These data can be recast to expose the differing effects of solvent on yield suppression with each terminator (Scheme 8-30). With either 106 or 107, the yield of macrocycle 94 was greater in benzene than in methyl isobutyrate. Thus, intermolecular trapping of an intermediate template-bound radical is less significant in benzene than in methyl isobutyrate. In these experiments, the differences are large (-20%) and suggest that a template-bound radical (e.g., 99) is not as accessible to either added terminator, 106 or 107, in benzene as it is in methyl isobutyrate. 100

benzene

80 -3

Z

5-

e 3

-

a

60 40

8 20

0

0

I

1

I

I

I

2 3 4

I

I

I

I

I

I

5 6 7 8 9 10 11 equiv 10 6

0

1 2

3 4 5 6 7 equiv 107

8 9 10' I

Scheme 8-30 Template macrocycle 94 yield as a function of solvent (benzene or methyl isobutyrate) in the presence of increasing amounts of the added terminators 106 and 107.

8.4 Concluding Remarks

243

Taken together, these results support an interpretation of the template controlled freeradical oligomerization of MMA in benzene that cites a solvent-induced steric effect in favoring intramolecular termination over bimolecular reaction. Specifically, a solvophobic effect [57-601 may force the growing hydrocarbon-like pMMA chain against the hydrocarbon-like template in benzene. This solvent enforced proximity of reactive entities in 99 may then contribute to an unexpected acceleration of macrocyclization compared with the alternative of further monomer addition. Consistent with this hypothesis, Endo et al. have shown that the relative energy of interaction between two phenyl rings is substantially larger than the energy of interaction of a phenyl ring with a hydrocarbon chain (Table 8-1) [60]. Thus, benzene’s affinity for itself may lead to “sequestering” of the hydrocarbon portions of 99, and in so doing enhance intramolecular reaction compared with a non-aromatic solvent. Table 8-1 Relative interaction energies between a phenyl ring and various hydrocarbon species (the more negative the value, the stronger the interaction) [60] Solvent

Relative energy of interaction with a phenyl ring (kcal/mol)

Anisole Benzene Cyclohexane n-Hexane n-Octane

-1.32 -0.44 -0.04 0.00

-1.51

Finally, the diastereomer distribution for macrocycle 94 was examined in each of the experiments reported in Schemes 8-29 and 8-30. While some variation was observed from run to run, no meaningful trends could be discerned. There is no evidence that certain stereoisomers of radical 99 are intrinsically slower to cyclize and hence would be more susceptible to trapping by 106 or 107.

8.4

Concluding Remarks

The successful demonstration of oligoselective free-radical polymerizations of acrylate and methacrylate monomers by the template constructs 14,24,40, 63, and 64 establishes the feasibility of this venture. In each case, optimization of both reaction parameters and template attributes led to very low-dispersity oligomers incorporating by design either n=2, n=3, or n = 4 monomer units. Yields were tolerable, given the number of new C-C bonds formed and the complexity of the transformations. Furthermore, differing strategies for stereocontrol revealed that stereoselective and oligoselective polymerizations are within reach. These preliminary experiments hint at the possibility that future studies may advance these techniques to the point where they will be valuable assets in the synthesis of stereodefined repeating molecular segments of target molecules.

244

8 Template Controlled Oligomerizations

8.5 Experimental Procedures 8.5.1 (2R,4S)- and (2S,4S)-2-(5-Bromopentyl)-2-methyl-3-acryloyl4-tert-butyl oxazolidine (23) 7-Bromo-2-heptanone (208 mg, 1.08 mmol) and tert-leucinol (1 89 mg, 1.61 mmol) were dissolved in benzene (1 0 mL). Catalytic TsOH was added, and the mixture was refluxed, with a Dean-Stark trap containing molecular sieves, for 18 h. The reaction solution was cooled to rt, solid NaHCO, was added, and the mixture was poured into saturated NaHCO, solution (200 mL) and extracted with ether (2 x 200 mL). The organic extracts were dried over Na,SO,, filtered, and condensed to a pale yellow oil which was dissolved in CH2C12(5.0mL) and used in the next step. The solution was cooled to 0 "C, triethylamine (0.24 mL, 1.7 mmol) and DMAP (3 mg) were added, followed by freshly distilled acryloyl chloride (0.123 mL, 1.51 mmol). The mixture was allowed to warm to rt over 12 h, diluted with CH2Cl, (50 mL) and washed with saturated NaHCO, solution (3 x 10 mL). The organic layer was dried over Na2S0, and condensed to a yellow oil which was purified by column chromatography (10% EtOAc/hexane) to give a combined yield of 195 mg (52%) of two diastereomers. First eluting diastereomer: R, 0.20 (20% EtOAdhexanes); 'H-NMR 6 6.51 (dd, J = 16.6, 10.0 Hz, lH), 6.33 (dd, J = 16.6, 1.9 Hz, lH), 5.60 (dd, J = 10.0, 1.9 Hz, IH), 4.40 (d, minor rotamer), 3.99 (d, IH), 3.89 (m, lH), 3.75 (d, IH), 3.45 (t, 2H), 2.42 (m, 1H diastereotopic), 1.85 (m, 2H), 1.68 (s, 3H), 1.6-1.2 (b, 5H), 0.95 (s, 9H), 0.92 (s, minor rotamer); 13C-NMR 6 164.90, 130.69, 127.36, 98.24, 65.38, 64.80, 35.89, 34.65, 33.82, 32.68, 28.29, 27.67, 27.32, 23.98; GC/CIMS (CHJNH,) m/z 347 (MH+). Second-eluting diastereomer: R , 0.10 (20% EtOAc/hexanes); 'H-NMR 66.51 (dd, J = 16.6, 10.0 Hz, IH), 6.34 (dd, J = 16.6, 1.9 Hz, lH), 5.63 (m, lH), 4.1 -3.7 (set of 3 multiplets, 3H), 3.38 (t, 2H), 2.58 (m, 1H diastereotopic), 1.85 (m, 2H), 1.51 (s, 3H), 1.6-1.2 (b, 5H), 0.95 (s, 9H); I3C-NMR 6 165.05, 130.76, 127.30, 98.04, 65.12, 64.64, 39.05, 35.70, 33.79, 32.61, 28.42, 27.68, 23.58, 19.69; GC/CIMS (CH,/NH,) mlz 347 (MH+).

8.5.2 1,2-Bis-[3,4-bis-(5-(2R-methyl-3-acryloyl-4S-tert-butyl2-oxazolidinyl)-pentyloxy)]-ethane(24) The following procedure is representative for the synthesis of the n = 4 templates. Tetrol 22 ( 1 10 mg, 0.33 mmol) and 23 were dissolved in acetone (3.5 mL) and distilled DMSO (1.5 mL). The solution was charged with K2C0, (273 mg, I .98 mmol) and catalytic [ 18lcrown-6 and brought to reflux for 18 h. The reaction mixture was cooled, extracted with ether (2x50 mL) and washed with saturated NaCl solution (2x 100 mL). The organic extracts were pooled, dried over Na,SO,, filtered, and condensed to a viscous oil which was purified by column chromatography (50% EtOAc/hexane) to give 24 as 204 mg (44%) of a colorless oil: R , 0.32 (50% EtOAdhexanes); 'H-NMR 6 7.61 (dd, J=8.1, lSH~,2H),7.49(d,J=lSH~,2H),6.81 (d,J=8.4Hz,2H),6.52(dd,J=16.6, 9.9 Hz, 4H), 6.33 (dd, J = 16.6, 1.8 Hz, 4H), 5.64 (dd, J=9.9, 1.8 Hz, 4H), 4.59 (s, 4H),

8.5 Experimental Procedures

245

4.00-3.87 (m, 16H), 3.79-3.69 (m, 4H), 1.80-1.53 (b, 16H), 1.71 (s, 12H), 1.45-1.30 (b, 16H), 0.93 (s, 36H, major), 0.90 (s, minor); 13C-NMR 6 166.25, 164.91, 153.26, 148.42, 130.77, 129.72, 127.30, 123.81, 114.24, 111.90, 98.31, 69.07, 68.70, 64.79, 62.41, 39.63, 35.91, 34.78, 29.15, 27.69, 27.35, 24.05. Analysis: Calcd. for CsOH122016N4: C, 68.83; H, 8.81; N, 4.01. Found: C, 69.08; H, 8.71; N, 3.74%.

8.5.3

-pica1 conditions for ACT reaction (2.5A/801/200s")

8.5.4

Telomer assay

From a benzene stock solution of template 14 (m= 3, R = terf-Bu), 0.0625 mmol(87 mg) of 14 was delivered to a reaction flask charged with cyclohexyl iodide (0.258 mL, 2.0 mmol, 32 equiv) and allyltributylstannane (1.55 mL, 5.0 mmol, 80 equiv) and the reaction diluted to a total volume of 25 mL in benzene. The reaction flask was purged with argon for 30 min, and then the mixture was brought to reflux. An initial portion of AIBN (2 mg, 0.0 125 mmol, 0.2 equiv) was added upon reflux, a second portion was added after 2 h, and reflux was maintained for another 10 h. The mixture was cooled to rt and the solvent carefully removed under reduced pressure. The residual oil was subjected to column chromatography using gradient elution (100% hexanes + 5%, lo%, 15%, 25%, 50%, 75% + 100% EtOAc), and the isolated products were dissolved in ether (50 mL) and stirred overnight over an aqueous 10% KF solution (50 mL). The layers were separated, and the organic layer was dried over MgSO,, condensed to a mixture of oils and solids, redissolved in EtOAc (5.0 mL), refiltered, and condensed to an oil.

The isolated oil was mixed with 1 M HCI(3.0 mL) andp-dioxane (3.0 mL) and refluxed at 100 "C for 12 h. The reaction mixture was poured into 1 M KOH (100 mL) and washed with ether (50 mL). The aqueous layer was cooled in an ice bath and acidified with conc. HC1 (approximately 10 mL), followed by stirring for 2 h with ether (50 mL) while saturating the aqueous layer with NaC1. The layers were separated, and the aqueous layer was further extracted with ether (2 x 25 mL). The pooled ethereal layers were dried over MgS04, filtered, condensed to a total volume of approximately 5.0 mL, and treated with an excess of diazomethane (generated from 0.5 g Diazaid). Excess diazomethane was quenched with a minimum amount of glacial acetic acid and the solution was washed with saturated NaHC03, dried over MgSO,, and filtered. The filtrate was analyzed by GC (1.0 min at 80 O C , ramp at 15 "C/min to 300 "C, and hold for 5.0 min; calibrated vs. an authentic mixture of methyl acrylatetelomers) and assignments were confirmed by GUMS.

8.5.5

Synthesis of Template Diester 48

A solution of norbornadiene (43) (85.4 g, 927 mmol) and NiCOD, (1.3 g, 4.73 mmol) in 100 mL of 1 ,Cdioxane was stirred at rt for 22 h, leading to deposition of a white precip-

itate. A second charge of norbornadiene (85.4 g, 927 mmol) was added, and the hetero-

246

8 Template Controlled Oligomerizations

geneous reaction mixture was warmed to 50-55 "C for 48 h and then at 40 "C for 16 h. Concentration of the reaction solution and fractional sublimation of the residue at 0.05 Torr afforded 96.6 g of dimer 44 at 60-70 "C (57%), 59.2 g of trimer 45 at 155-165 "C (34%), and 5.8 g of tetrarner 44 at 240°C (3%). The trimer was recrystallized from hot isopropanol to furnish 47.8 g of 45 as fluffy white crystals; m.p. 198-201 "C (lit. [49] m.p. 201 "C); IR (CDCl,) 3035, 1610 cm-'; 'H-NMR (200 MHz, CDCI,) 6 5.93 (s, 4H), 2.59 (s, 4H), 1.89-1.12 (m, 16H); 13C-NMR(90 MHz, CDCl,) 6 135.3,44.2,41.8,41.6,40.6,28.9; MS mlz (relative intensity) 276 (100, M+). A solution of NBD trimer 45 (11 g, 40 mmol), methyl 9-anthracenecarboxylate (47) (20 g, 85 mmol), and 3-tert-butyl-4-hydroxy-5-methylphenylsulfide (20 mg, 0.06 mmol) in 50 mL of benzene was heated to 170 "C in a steel-walled medium-pressure reactor. After 200 h, the solution was cooled, concentrated in vacuo, and the residue was purified by flash chromatography on SO, with 3 : 1 benzenehexane as eluent to afford 12.5 g (43%) of the C, template diester 48 and 13.5 g (47%) of the template C, diester 49. Both solids decomposed upon heating (48: 256"C, 49: 338°C). 48: IR (CDCIJ 1730crn-I; 'H-NMR (200 MHz, CDC1,) 6 7.51-6.96 (m, 16H), 4.17 (d, J=2.2Hz, 2H), 4.05 (s, 6H), 2.04-1.05 (m, 22H), -0.61 (d, J = 10.2 Hz, 2H); I3C-NMR (90 MHz, CDCl,) 6 172.7, 143.7, 142.7, 141.6, 139.1, 126.5, 126.2, 126.0, 125.5, 124.3, 124.0, 123.0, 121.8, 58.8, 51.9, 49.4, 48.6, 48.4, 47.1, 47.0, 42.6, 42.30, 42.28, 41.5, 41.3,41.2, 29.0, 27.6; FABMS mlz (relative intensity) 747 (22, M-H').

8.5.6 Controlled Oligomerizationof Methyl Methacrylate with Template 63 A solution of 63 (80 rng, 0.078 rnrnol), Mo(CO)~(25 rng, 0.10 rnmol), and MMA (84 pL, 0.78 mmol) in 8 mL of benzene in a heavy-walled vessel equipped with a Teflon stopcock was deoxygenated by three freeze-pump-thaw cycles and placed in a 70 "C oil bath for nine days. At that time, the reaction was poured into 5 mL of 1 M HCl, and the aqueous layer was extracted with 4 x 10 mL of CH,CI,. The combined organic layers were washed with brine and dried over Na,SO,. Filtration, concentration, and purification of the residue by flash chromatography on SiO, with 2% Et20/CH2C12, 4% Et20/CH2C1,, 6% Et,O/CH,Cl, as eluent gave 43 mg (47%) of the template-bound MMA trimer 94 as a mixture of six isomers. This material could be further purified by HPLC (SiO,, 2% Et20/CH2C12eluent) to furnish six separate diastereorners of 94. 94 (major diastereomer): IR (CCl,) 1725 cm-'; 'H-NMR (400 MHz, CDCI,) 67.2-6.9 (m, 16H), 6.13 (d, J = 1.0 Hz, lH), 5.80 (d, J = 11.4 Hz, lH), 5.74 (d, J = 11.3 Hz, lH), 5.34 (s, lH), 4.91 (d, J = 11.7 Hz, lH), 4.88 (d, J = 12.0 Hz, lH), 4.17 (m, 2H), 3.65 (s, 3H), 3.60 (s, 3H), 3.53 (s, 3H), 3.06 (d, J = 14.4 Hz, lH), 2.48 (d, J = 14.9 Hz, IH), 2.41 (d, J=13.4 Hz, IH), 2.34 (d, J=13.2Hz, IH), 2.07 (d, J=14.2Hz, IH), 2.00 (d, J = 14.2 Hz, lH), 1.9-1.2 (m, 24H), 1.00 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H), -0.32 (m, 2H); 13C-NMR (100 MHz, CDC1,) 6 177.1, 175.9, 175.6, 167.9, 165.9, 145.1, 144.9, 143.6, 142.8, 142.7, 142.6, 141.3, 140.8, 137.3, 128.3, 126.3, 126.2, 126.0, 125.7, 125.6, 125.5, 125.4, 124.6, 124.5, 123.3, 121.0, 120.8, 120.5, 83.0,66.4, 62.5, 56.6, 53.2, 52.7, 52.2,51.9,51.6,48.4,48.2,48.1,47.9,47.8,47.7,47.6,47.5,47.4,47.2,46.9,45.6,44.5,

References

247

44.3, 42.6, 42.3, 42.1, 42.0, 41.9, 41.4, 39.8, 39.6, 29.0, 28.5, 28.3, 17.7, 16.7, 16.2; FABMS m/.. (relative intensity) 1172, 1171, 1170, 1169, 1168 (6, 9, 8,9,2 M + , M++1).

Acknowledgments The dedicated efforts of talented co-workers at Penn State (Dr. Yoon Lee, John Bobo, Dr. Gregory Tewalt, Dr. William Shiang, Paul Weinreb and Susan Ensel) and at Duke (Greg Miracle and Scott Cannizzaro) are gratefully acknowledged, as is financial support from the National Science Foundation (Penn State and Duke) and the National Institutes of Health (Duke).

References [ 11 D. P. Curran, N. A. Porter, B. Giese, Control of Stereochemistry in Free Radical Reactions;

Concepts, Guidelines, and Synthetic Applications, VCH: Weinheim, 1995. [2] K. Mori, S. Kuwahara, Tetrahedron 1986,42,5539-5544. [3] M. Kaino, Y. Naruse, K. Ishihara, H. Yamamoto, J. Org. Chem. 1990,55,5814-5815. [4] T. I. Richardson, S. D. Rychnovsky, J. Am. Chem. SOC. 1997,119, 12360- 12361. [ 5 ] D. P. Curran, “Radical Addition Reactions,” and “Radical Cyclization Reactions and Sequential Radical Reactions.” In Comprehensive Organic Synthesis; B. M. Trost, I. Fleming, Eds.; Pergamon: Elmsford, NY, 1991; Vol.4, Chapters 4.1 and 4.2. [6] N. A. Porter, D. P. Curran, B. Giese, Acc. Chem. Res. 1991, 24, 296-304, and references therein. [7] J. H. Wu, R. Radinov, N. A. Porter, J. Am. Chem. SOC.1995, I1 7, 11029- 11030. [8] M. P. Sibi, J. Ji, J. H. Wu, S. Giirtler, N. A. Porter, J. Am. Chem. SOC.1996,118, 9200-9201. [9] D. Nanni, D. P. Curran, Tetrahedron-Asymmetry 1996,8,2417-2422. [lo] M. Blumenstein, K. Schwarzkopf, J. 0. Metzger, Angew.Chem. 1997,36,235-236. [Ill M. P. Sibi, J. Ji, J. Org. Chem. 1997,62, 3800-3801. 1121 M. Murakata, T. Jono, Y. Mizuno, 0. Hoshino, J. Am. Chem. SOC. 1997, 119, 11713-11714. 1131 For a historical perspective, see: G. S. Miracle, S. C. Cannizzaro, N. A. Porter, ChemTructs 1993, 147-171. [I41 N. A. Porter, G . S. Miracle, S. C. Cannizzaro, R. L. Carter, A. T. McPhail, L. Liu, J . Am. Chem. SOC.1994,116,10255-10266. [15] G. S. Miracle, S. C. Cannizzaro, N. A. Porter, J. Am. Chem. Soc. 1992,114,9683-9684. [16] K. S. Feldman, Y. B. Lee, J. Am. Chem. SOC. 1987,109,5850-5851. [I71 K. S. Feldman, J. S. Bobo, S. M. Ensel, Y. B. Lee, P. H. Weinreb, J. Org. Chem. 1990, 55, 474 -48 1. 1181 K. S. Feldman, J. S. Bobo, G. L. Tewalt, J. Org. Chem. 1992,57,4573-4574. 1191 N. A. Porter, D. R. Magnin, B. T. Wright, J. Am. Chem. SOC. 1986,108,2787-2788. [20] N. A. Porter, V. H.-T. Chang, J. Am. Chem. SOC. 1987,109,4976-4981. [21] N. A. Porter, V. H.-T. Chang, D. R. Magnin, B. T. Wright, J . Am. Chem. SOC. 1988, 110, 3554-3560. [22] N. A. Porter, “Stereochemical and Regiochemical Aspects of Free Radical Macrocyclizations.” In Organic Free Radicals; Proceedings of the Fifth International Symposium; H. Fischer, H. Heimgartner, Eds.; Springer: Berlin, 1988; p. 187.

248

8 Template Controlled Oligomerizations

[23] N. A. Porter, B. Lacher, V. H.-T. Chang, D. R. Magnin, J. Am. Chem. Soc. 1989, 111, 8309-8310. [24] H. Karnmerer, S. Ozaki, Makrumol. Chem. 1966,91, 1-9. [25] H. Kammerer, A. Jung, Mukromol. Chem. 1967,101,284-295. [26] H . Kammerer, A. Jung, J. S. Shukla, Mukromol. Chem. 1967, 107, 259-261. [27] W. Kern, H. Kammerer, Pure Appl. Chem. 1967, 15,421-433. [28] H. Kamrnerer, N. Onder, Makromol. Chem. 1968,111,67-73. [29] H. Kammerer, J. S. Shukla, Makromol. Chem. 1968, 116, 62-71. [30] H. Karnrnerer, J. S. Shukla, G. Scheuerrnann, Makromol. Chem. 1968,116.72-77. [31] H. Karnmerer, G. Hegemann, Makrumol. Chem. 1970,139, 17-21. [32] H. GuCniffey, H. Kammerer, C. Pinazzi, Mukromol. Chem. 1973, 165,73-81. [33] H. Kamrnerer, G. Hegemann, Makromol. Chem. 1982,183, 1435- 1444. [34] H. Kamrnerer, G. Hegernann, Makromol. Chem. 1984,185,635-646. [35] N. A. Porter, J. D. Bruhnke, W.-X. Wu, I. J. Rosenstein, R. A. Breyer, J. Am. Chem. Soc. 1991,113,7788-7790. [36] N. A. Porter, W.-X. Wu, A. T. McPhail, Tetrahedron Lett. 1991,32, 707-710. [37] N. A. Porter, I. J. Rosenstein, R. B. Breyer, J. D. Bruhnke, W.-X. Wu, A. T. McPhail, J. Am. Chem. Soc. 1992,114,7664-7676. [38] K. E. Harding, C. Tseng, J. Org. Chem. 1978,43,3972-3977. [39] The source of H-atoms has not been identified, but the position (11to the phenolic ether would be reactive toward electrophilic or ambiphilic radicals. [40] H. Girard, P. Monjol, C. R. Hebd. Seances. Acad. Sci., Sel: C (Paris) 1974, 553-555. [41] K. Matsuzaki, T. Uryu, A. Ishida, M. Takeuchi, T. Ohki, Pulym. Sci. Part A-1 1967, 5, 2 167-2 177. [42] N. A. Porter, T. Allen, R. B. Breyer, J. Am. Chem. SUC. 1992,114,7676-7683, and references cited therein. [43] A. Philippon, M. Degueil-Castaing, A. L. J. Beckwith, B. Maillard, . I Org. . Chem. 1998,63, 6814-68 19. [44] G. Illuminati, L. Mandolini, Acc. Chem. Rex 1981, 14,95- 102. [45] D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991,113,7277-7287. [46] R. E. Ireland, L. Lui, J. Org. Chem. 1993,58,2899-2903. [47] S. D. Meyer, S. L. Schreiber J. Org. Chem. 1994,59,7549-7552. [48] Radical stabilization energies for radicals a to ethers have been estimated at 12 kcal/mol. E G. Bordwell, X.-M. Zhang, M. S. Alnajjar, J. A. Franz, J. Org. Chem. 1995,60,4976-4979. [49] R. L. Pruett, E. A. Rick, US Patent 3440294, April 22, 1969. [50] U. Azzena, S. Cossu, 0. De Lucchi, G. Melloni, Gazz. Chim. Ital. 1989,119,357-358. [51] R. N. Warrener, I. G. Pitt, D. N. Butler, J. Chem. SOC.,Chem. Cummun. 1983, 1340-1341. [52] R. N. Warrener, D. N. Butler, R. A. Russell, SynLett 1998,566-573. [53] C. H. Barnford, R. W. Dyson, G. C. Eastmond, D. Whittle, Polymer 1969, 10,759-770. [54] D. Y . Sogah, W. R. Hertler, 0. W. Webster, G. M. Cohen, Macromolecules 1987, 20, 1473- 1488. [55] E. P. Boden, G . E. Keck, J. Org. Chem. 1985,50,2394-2395. [56] P. J. Wagner, J. H. Sedon, M. J. Lindstrom, J. Am. Chem. SOC. 1978,100,2579-2580. [57] M. H. Abraham, J. Am. Chem. Soc. 1982,104,2085-2094. [58] T. Dunarns, W. Hoekstra, M. Pentaleri, D. Liotta, Tetrahedron Lett. 1988, 29, 3745-3748. [59] R. Breslow,T. Guo, J. Am. Chem. SOC. 1988,110,5613-5617. [60] M. M. Itoh, J-i. Kato, S. Takagi, E. Nakashiro, T. Sato, Y.Yamada, H. Saito, T. Namiki, I. Takarnura, K. Wakatsuki,T. Suzuki,T. Endo, J. Am. Chem. Soc. 1988,110,5147-5152.

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

9 Templated or Not Templated, That is the Question: Analysis of Some Ring Closure Reactions Alois Fiirstner

9.1 Introduction Searching for the entries “template” or “templated’ in the common chemical databases makes clear that these expressions are widely used but very ill defined. If we understand a template as a molecular device which shapes a given substrate and thereby provides bias for a certain pathway over a competing one, and which is removed once it has exerted its function, we will have no problem in calling many ring closure reactions “template&’ ones. A prototype example of a cyclization using a covalently linked template is the Corey-Nicolaou method for macrolide synthesis (Scheme 9- 1) [ 11. This transformation takes advantage from the polyfunctional character of thiopyridyl esters which (i) activate the acid part, (ii) help to bring the reacting sites in proximity by an acid-base interaction, and (iii) activate the -OH group ifa reactive conformation is adopted. Similarly classical is crown ether formation by intramolecular substitution reactions, where a cation of appropriate size coordinates to the heteroatoms of the incipient ring and thereby allows cyclizations to occur at concentrations that are much higher than usual for systems of this size (Scheme 9-2) [2]. Finally, the cyclotrimerization of butadiene pioneered by Wilke and co-workers should be mentioned as an illustrative example of a catalytic, templated ring closure which crucially depends upon the assembly of the monomer units within the coordination sphere of a nickel template that changes its oxidation state and coordination number while running through the catalytic cycle (Scheme 9-3) [3]. In generalizing the latter examples one may be tempted to assume that all metal-assisted cyclization and cross coupling reactions are templated processes. This viewpoint, however, not only sets an impractically wide scope for a review, it may even be incorrect. Therefore, the present article does not try to cover all potentially “templated” ring closure reactions [4],but presents just a very limited and personal selection of metal-assisted or metal-catalyzed cyclizations based on C-C coupling reactions. They are analyzed with the intention to deduce more accurately what the phenomenological effect of templating refers to.

250

9 Templated or Not Templated, That is the Question

Scheme 9-2

9.2 Possible Pitfalls

25 1

9.2 Possible Pitfalls It is common knowledge that the preparation of medium-sized rings is a formidable challenge because unfavorable entropic and enthalpic factors impede their formation [ 5 ] . Therefore, many successful entries into this series rely on templates which lock the flexible substrate in a suitable conformation for ring closure and thereby increase the probability of encounters of the reacting sites. With this notion in mind, the surprising efficiency of the catalytic ring expansion depicted in Scheme 9-4, a key step in a recent total synthesis of the immunosuppressive alkaloid streptorubin B [ 6 ] ,might be ascribed to the well-known affinity of Pt" toward alkenes and alkynes which fosters the desired formation of the 10-membered ring in a cooperative manner. This analysis, though seemingly reasonable, is probably incorrect, During an in-depth study of the reaction mechanism it was found that the same transformation can also be effected in respectable yield with protons (!) instead of PtC12.Therefore one must conclude that the efficiency of this particular ring expansion mainly results from the geometrical constraints of the substrate rather than from a preorganization mediated by the catalyst. If any template effect is operative, it accounts only for the slightly higher efficiency of the PtC1,-catalyzed over the proton-induced pathway.

=" Ts

RC12 (5 mlY0)

toluene, 50°C

79%

1

HBF4

Scheme 9-4

toluene, 50°C 57%

Even in cases where the topology of a given substrate renders cyclization a priori rather unlikely, it is potentially misleading to invoke a template effect without appropriate control experiments. An illustrative example was reported by Negishi and co-workers (Scheme 9-5) [7]. Intramolecular carbopalladation reactions of w-haloallenes provide a

9 Templuted or Not Templuted, That is the Question

252

potentially general method for the synthesis of common, medium, and large rings. Therefore the efficiency of the conversion of substrate 3 into the eight-membered ring compound 6 could be attributed to coordination-induced proximity: oxidative insertion of Pd" into the aryl halide provides an arylpalladium(I1) species which coordinates the allene entity and thereby facilitates the C - C-bond formation despite of the unfavorable size of the incipient ring.

la1

..

52%

- & W

(74% by NMR)

3

4

6

.

5

[a] PdClz(PPh3)~(5 mol%), K&O3, EtOWDMF, 100°C Scheme 9-5

This scenario, however, does not explain why the cyclization of the corresponding whaloalkene 7 is terribly inefficient, although it might follow a similar course (Scheme 9-6); simple dehalogenation of the substrate rather than ring closure becomes the major pathway. This outcome indicates that factors other than the template effect of Pd" foster the allene case, which are not operative with the alkene. One may speculate whether kinetic parameters such as the generally higher reactivity of allenes toward organopalladium reagents caused by their higher strain energies, or if thermodynamic features such as the stability of the resulting a-allylpalladium species 5 formed by an irreversible C-C-coupling process drive the conversion of 3 4 6.

[a1 < 5% by NMR

7

[a] PdClz(PPh3)~(5 rnol%), kCO3, EtOWDMF, 100°C Scheme 9-6

8

9.3 Titanium-induced Intramolecular Carlmnvl Coitnlin P Keuctiom

25 3

These examples pinpoint the notions that (i) one must be very prudent in ascribing the performance of ring closure reactions to a template effect if the substrate contains any element of structural preorganization. The same caution applies - maybe even to a larger extent - to all cyclizations involving kinetically favorable ring sizes 181; (ii) control experiments are mandatory in order to distinguish between a possible tcmplate effect and other, more conventional incentives for ring closure.

In searching for templated cyclization reactions it is therefore best to look at substrates which are as flexible as possible in order to rule out any potentially misleading inlluence of simple geometrical constraints. For the same reason, macrocycle syntheses rather than the formation of five- to seven-membered rings are generally more suitable for studying a possible template effect, since the proximity of the reacting sites in the required precursors is a priori less likely [9]. Therefore the following discussion is restricted to some examples of ring closure reactions by metal-induced C-C-bond formation which meet these criteria and for which direct rather than presumptive evidence is available that a template effect is in fact operative.

9.3 Titanium-induced Intramolecular Carbonyl Coupling Reactions The reductive coupling of carbonyl compounds by means of low-valent titanium [Ti], a process which is generally referred to as the McMurry reaction in honor of one of its pioneers, has attracted considerable attention over recent decades [lo]. One of its major advantages stems from the fact that this transformation makes it possible to form carboand heterocycles of any ring size, including medium and macrocyclic ones. This feature is witnessed by a considerable number of elegant syntheses of natural and non-natural products and has often been ascribed to the template effect exerted by the polar surface of the low-valent titanium reagents used. Several pieces of evidence - in fact - support this argument. Specifically, McMuny et al. [ 1I] and Baumstark et al. [ 121 have systematically investigated the intramolecular coupling of a homologeous series of conformationally flexible dicarbonyl compounds by means of [Ti] derived from either TiCl,/Li or TiCI,/LiAIH,. These early studies have shown that the yield of the cycloalkenes formed is essentially independent of the ring size (Table 9-l), an outcome that is in clear contrast to the profile of most other classical cyclization reactions. For comparison, the Dieckmann condensation of diesters or the Thorpe-Ziegler dinitrile method fail to afford medium-sized rings in reasonable yields and perform only poorly in the macrocyclic series [ 13, 1.51. Even the acyloin condensation [I'!], which was one of the first reasonable entries into products with 8-11 ring atoms, does not show the same striking uniformity as the titanium mediated process.

254

9 Templated or Not Templated, That is the Question

Table 9-1 Effect of the ring size on intramolecular, low-valent titanium-induced carbonyl coupling reactions.

R'

R2

n

Yield (%)

Ref.

The experiments mentioned above have been carried out under high dilution, i.e., conditions which are known to favor cyclization over competing intermolecular reactions [ 15, 161. Even more surprising are reports on McMurry-type macrocyclizations which deliberately disregard the "Ziegler-Ruggli dilution principle" [ 15, 161 but still provide good to excellent results. One of the most striking examples is the formation of a 36membered ring depicted in Scheme 9-7, where the conformationally flexible substrate 9 is converted into product 10 in 90% yield when exposed to a refluxing slurry of commercial titanium powder activated by TMSCl even if its concentration is as high as 0.02 M [17]. This outcome indicates an exceptional preference for ring closure which must be attributed to a preorganization of the diketone by the chemically activated titanium surface [18]. Similar observations have been made during a study on the formation of crownophanes such as 14 (Scheme 9-8) which proceed smoothly even in rather concentrated solutions [ 191. In this particular case, photochemical control experiments provide strong evidence that the titanium mediated process benefits from a significant template effect. Whereas the photoinduced intramolecular pinacolization of diketone 11 to diol 12 in 0.002 M solution is rather inefficient (= 29%) [20], treatment of the same substrate with

9.3 Titanium-inducedIntramolecular Carbonyl Coupling Reactions 0

9

commercial Ti-powder, TMSCI

t

dimethoxyethane, reflw 90%

10

Scheme 9-7

11

0.02 M in THF

12

l3

Scheme 9-8

I

255

256

9 Templated or Not Templated, That is the Question

[Ti] leads to the desired 20-membered ring 14 in 57-83% yield by deoxygenation of an intermediate titanium pinacolate 13 at concentrations 2 0.02 M ! One may, however, object that this outcome is not due to a template effect of [Ti] but rather to the considerable amounts of (alkali) metal salts such as KC1, LiCl, MgCl,, ZnC12, or AlCl, accumulating in the reaction mixture during the preparation of the [Ti] reagent from TiC1, or TiCl, and Li, K, Mg, Zn, LiAIH,, etc.; these salts may preorganize the polyether substrate as shown in Scheme 9-9 and thereby facilitate the cyclization process.

Scheme 9-9

A series of experiments, however, using (i) different [Ti] species, including titanium activated under “salt-free’’ conditions (Ti/TMSCl) [ 17, 181, and (ii) different substrates with and without polyether chains, made it possible to distinguish between the effect of [Ti] and that of the admixed salts. From the results summarized in Table 9-2 it must be deduced that [Ti] is largely responsible for the smooth cyclizations, whereas the admixed salts play only a minor role. The much more intricate question, however, of how this striking property of [Ti] can be explained on the molecular level, is largely unsolved. The heterogeneous character of McMuny reactions makes spectroscopic investigations rather difficult, and all mechanistic studies are further hampered by the fact that [Ti] exhibits a much more complicated inorganic chemistry than was previously anticipated [211. One can, however, safely pretend that the pronounced oxophilicity of titanium is the chemical basis for the observed template effect. As mentioned above, the coupling of carbonyl compounds, which proceeds via ketyl radical anions as the actual intermediates, occurs smoothly in an inter- as well as an intramolecular manner and is largely unaffected by the ring size formed. In stark contrast, the titanium mediated coupling of allylic alcohols is only productive as an intermolecular process, whereas the intramolecular variant fails to afford reasonable amounts of macrocyclic products (Scheme 9-10) [22]. This difference can probably be explained by assuming that free ally1 radicals are formed in the latter case which cannot stick to [Ti] as they lack the oxygen atom of their ketyl analogues. Rather than being preorganized in a favorable conformation for ring closure on the oxophilic surface of the reagent, they diffuse freely in solution and get reduced by hydrogen abstraction from the ethereal medium.

9.3 Titanium-induced Intramolecular Carhonyl Coupling Ketrctiom

251

Table 9-2 Probing the template effect of low-valent-titanium [Ti] and admixed alkali halide\ L191. Product

a: \

Ph

[Ti1

Admixed salt

Yield ( % )

TiC1,/2 C8K

KCI

81

TiC1,/2 Na

NaCl

83

Ti/TMSCI

-

57

TiC13/2 C8K

KCI

86

TiC1,/2 Na

NaCl

86

TiCI3/2 C8K

KCI

63

Ti/TMSCI

-

60

16

-1 Scheme 9-10

I

a 80%

17

258

9 Temdated or Not Temulated. That is the Ouestion

9.4 Zinc versus Samarium Mediated Reformatsky Reactions According to a general definition, the Reformatsky reaction can be taken as subsuming all enolate formations by oxidative addition of a metal or a low-valent metal salt into a carbonhalogen bond activated by a vicinal carbonyl group, followed by reaction of the enolates thus formed with an appropriate electrophile [23].The insertion of metallic zinc into a-halo esters is historically the first and still the most widely used form of this process although Zn may be beneficially replaced but other metals and reducing metal salts in certain cases. A particular advantage of the Reformatsky reaction stems from the fact that the site of reaction is strictly determined by the halogen moiety. This feature can be advantageously used for regioselective enolate formations in polycarbonyl compounds which are difficult to achieve by proton abstraction methods. As a consequence, this transformation has seen a renaissance over recent decades and has found many elegant uses, particularly in intramolecular variants [23]. The traditional zinc mediated process, though well suited for the formation of fiveand six-membered rings, performs rather poorly in the more challenging macrocyclic series [24]. This limitation, can be overcome by replacing Zn by SmI, as the reagent [25]. Comparative data using the conformationally flexible substrate 18 show that the latter provides excellent yields whereas Zn does not afford preparatively useful results (Scheme 9-11). This outcome probably stems from the high oxophilicity and the flexible coordination geometry of the Sm3+counterion to the enolate, which acts as a template and coordinatively binds the aldehyde group in a much tighter transition state than Zn2+ does. Applications to the synthesis of complex natural products such as ferrulactone [26], octalactin A21 [27], and Taxol@[28] (Scheme 9-12) witness the truly remarkable efficiency of such intramolecular Sm12 mediated Reformatsky variants. From the examples compiled in this and the previous sections one must conclude that the ufJiity of certain transition metals towards oxygen-containing functional groups can be macroscopically expressed as a template effect in ring closure reactions.

Scheme 9-11

1

19

J

9.5 Macrocycle Syntheses by Ring CIosirig Metathesis (RCM)

60%

259

Ferrulactone I

0

(-)-OctalacrinA

9.5 Macrocycle Syntheses by Ring Closing Metathesis (RCM) Formally speaking, the cyclization of a dicarbonyl compound to a cycloalkene via a McMurry coupling closely resembles the ring closing metathesis (RCM) of a 1 ,o-diene, although these reactions have nothing in common as to their mechanisms (Scheme 9-13) [29,30]. Whereas the former has recently been recognized as a very efficient entry into macrocycles due to the inherent template effect of [Ti] discussed in Section 9-3, the latter transformation has long been thought to be inappropriate for the formation of large rings, except for systems which are a priori strongly biased for ring closure by a rigid conformation of the diene substrate [31]. This assumption, however, has been totally revised in recent years: surprisingly enough, RCM turned out to be among the best entries into macrocycles even with conformationally flexible diene substrates, provided that a few basic parameters are properly assessed [32]. These key features indicate that a subtle template effect is responsible for the effectiveness and scope of RCM-based ring closure reactions.

9 Templated or Not Templated, That is the Question

260

Specifically, the entirely different behavior of dienes 21 and 23 (Scheme 9-14) shows that the presence of a polar functional group in the substrate is a fundamental requirement for productive macrocyclization [32]. In addition, the distance of the polar substituents from the dienes to be metathesized turned out to be another decisive factor, as can be gleaned from Scheme 9-15 [32].

\/\// 22

21

[a1

D

oligomers

23

Scheme 9-14

9.5 Macrocycle Syntheses by Ring Closing Metathesis (RCM)

26 I

110 reaction

25

‘

26

‘

[a] (C~~P)ZC~ZRU=CHCH=CP~ 2, 5 mol%

Scheme 9-15

These observations are best rationalized in terms of coordination of the emerging carbene and/or metallacyclic intermediates of the metathesis reaction with the polar “relay” substituents of the substrate [32]. Such a Lewis-acidhwis-base interaction assists in assembling the reacting sites within the coordination sphere of, e.g., the ruthenium catalyst and hence provides the necessary bias for cyclization asformally depicted in Scheme 9-17. If, however, such an intermediate becomes too stable, as might be the case for some five- or six-membered chelate structures (e.g., structures B and C or similar), the catalyst is sequestered in an unproductive form and the conversion is likely to cease. Yet, the stability of the assumed intermediates is not only defined by geometric parameters such as distance and relative orientation, but will also be very strongly influenced by the affinity of the “soft” Ru center to the heteroatom. This explains why the presence of sulfur(II), amino and cyano groups usually stops RCM events catalyzed by standard Grubbstype complexes such as (PCy&Cl,Ru =CHR (R = Ph, CH = CPh,) (Scheme 9- 16) [33, 34dl. Although the experimental data summarized above provide convincing evidence that a subtle and transient template effect resulting from a finely tuned Lewis-acid/Lewisbase interaction is operative in productive RCM-based macrocyclizations, it should be emphasized that a detailed spectroscopic characterization of the key intermediates involved has not yet been achieved. Therefore structure A represents just a mnemotic device indicating that polarity, distance, and affinity are key issues in such transformations but does not imply any structural information [32]. Although this “relay model” is rather simple, it provides a safe guidance for retrosynthetic planning and its predictive capacity has been successfully tested in numerous applications. Scheme 9-18 compiles some of the targets which have been obtained in our laboratory so far [34], which are supplemented by many additional examples from other

9 Templated or Not Templated, That is the Question

262

__t

Me0 \ \

27

28

[a] (Cy3P)2Cl&=CHCKCPh

2 (cat.)

Scheme 9-16

L A

B

C

Scheme 9-17

groups [35]. The synthesis of (-)-gloeosporone is particularly informative, as it forced us to address and overcome a potential limitation of RCM-based macrocyclizationprocesses [36]. (-)-Gloeosporone 31 is a germination self-inhibitor produced by the fungus Colletotrichurn gloeosporoides, which has attracted attention because of its interesting structural and biological properties [37]. While all previous syntheses of 31 are based on macrolactonization strategies, RCM might enable a conceptually new and unprecedentedly short approach to this macrolide as depicted in Scheme 9-19.

Y.5 Macrocycle Syntheses by Ring Closing Metuthesis (RCM)

(q

(+)-LasiodiplOdin

Dactyl01

263

Jasmin Kelolactone

OH

Zearanol

Epilachnene

(-)-Gloeosporone

Cyclomnylprodigiosin / NH

Roseophilin

TricolorinG

Scheme 9-18

A more detailed assessment of this retrosynthetic scheme, however, reveals a potential difficulty, if the “relay model” outlined above is valid. Assuming that the catalyst attacks the 4-pentenoate entity of the envisaged cyclization precursor 34, a fairly stable s i x membered chelate structure may be obtained which can intercept the catalyst in an unproductive form.

9 Temnlated or Not Temdated. That is the Ouestion

264

9

OH

31

33

B 32

34

I

Scheme 9-19

In fact, diene 34, which is easily obtained in enantiomerically pure form from cycloheptene, fails to afford any cyclized product on exposure to catalytic amounts of the ruthenium carbene (PCy3),C1,Ru= CHPh. We reasoned that it is necessary to destabilize the likely unproductive chelate responsible for this outcome and/or to activate the catalyst. Either goal might be achieved by running the reaction in the presence of a Lewis acid which competes with the evolving carbene for the Lewis-basic ester group and/or will interact with (PCy,),Cl,Ru=CHPh, e.g., by abstraction of a basic phosphine ligand. The additive, however, must not destroy the catalyst, should cause a minimum of acid catalyzed side reactions, and - most importantly - should undergo a kinetically labile coordination to the ester. We identified Ti(OiPr), as a candidate which meets these stringent criteria. Gratifyingly, exposure of diene 34 to a mixture of catalytic amounts of (PCy,),Cl,Ru=CHPh and substoichiometric amounts of Ti(OiPr), in refluxing CH,Cl, effects a smooth cyclization reaction (Scheme 9-20)! The resulting product 35 is then oxidized to vic-diketone 36 with KMnO, in Ac,O, which on cleavage of the silyl protecting group during the aqueous workup cyclizes to (-)-gloeosporone 31. This approach delivers enantiomerically pure 31 in only eight synthetic operations with excellent overall yield starting from cycloheptene; moreover, the chosen route is highly flexible and can be easily adapted to the synthesis of analogues of this bioactive target. Although the precise mode of action of the binary RCM catalyst (i.e., (pCy3)2C12Ru=CHPh +Ti(OiPr),) remains to be elucidated, its key role within the gloeosporone synthesis gives further credence to the notion that a transient and kinetically labile chelate complex acts as a crucial template which shapes the diene precursor and thereby provides internal bias for ring closure.

9.6 Macrocvcles via Twii-Trost Allvlutioti

265

PCY3

06 steps

c L,,,,I 0

OTBS

>!,at’cl t

t Ti(OiPr)4 cat. 80%

34

H

Scheme 9-20

31

9.6 Macrocycles via Tsuji -Trost Allylation The comparison of intramolecular carbopalladation reactions of allenes and alkenes outlined in Schemes 9-5 and 9-6 illustrates that not every transition metal catalyzed ring closure necessarily involves a template effect. Others, however, clearly benefit from it. A prototype example is the palladium catalyzed cycloisomerization of alkenyl epoxides carrying distal pre-nucleophiles [38, 391, representing one variant of the famous Tsuji-Trost allylation [40]. This particular transformation cleverly exploits the polyfunctional character of the reacting units. It starts with an oxidative insertion of Pdo into the allylic moiety leading to the formation of a dipolar x-allylpalladium species. This step usually occurs with particular ease since the strain of the epoxide ring is released. The resulting alkoxide adjacent to the x-ally1 unit acts as a base and deprotonates the pre-nucleophile ifthe substrate adopts a suitable conformation. Charge attraction then keeps the emerging nucleophile in the proximity of the electrophilic a-allylpalladium entity, thereby greatly enhances the

266

9 Ternplated or Not Ternplated, That is the Question

chance of reactive encounters, and strongly favors the formation of the desired cyclic product. This intrinsic stabilization of the properly shaped conformer is macroscopically expressed in the ease of cyclization ascribed to a “template effect”. An additional advantage of this methodology stems from the fact that the hydroxyl group liberated during the oxidative insertion step directs the entering nucleophile to the distal position of the x-allylpalladium complex and therefore efficiently controls the regioselectivity of the reaction [38 -401. It should be mentioned, however, that high dilution is still mandatory in order to obtain high yields [15, 161, which can be achieved either by low feeding rates of the substrate into the solution containing the catalyst or by exploiting the “pseudo-dilution effect” of polymer bound Pdo [41]. This experimental requirement shows that the palladium center itself does not shape the substrate but just stabilizes the reactive conformation once it is adopted (Scheme 9-21). Therefore the observed “template effect” must be largely attributed to electrostatic attraction andor favorable ion pairing properties of the intermediates.

H

X

X X = COOMe, SQPh,CN etc.

Scheme 9-21

The key step of a recent total synthesis of roseophilin 41, a structurally unique alkaloid with promising cytotoxic activities, constitutes a characteristic example illustrating the performance of this process (Scheme 9-22) [42]. Thus, treatment of compound 38 with catalytic amounts of Pd(PPh& and dppe in refluxing THF leads to the formation of

9.6 Macrocvcles via Tsuii- Trost Allvlution

267

the highly functionalized 13-membered ring 39, which can be converted into the macrotricyclic ketopyrrole core 40 of the target in a few operations. It is interesting to note that the same compound has also been made by a ring closing metathesis route [43], with the yields of the palladium- and the RCM-based approaches being almost identical.

-

SOnPh

COOMe

tBuMePSiO II

38

37

Pd(0) cat.

85%

39

40

Scheme 9-22

A conceptually clos ly re12 d approach to medium-sized and large rings has been recently reported, in which the cyclization is triggered by a hydropalladation of an allene rather than by oxidative addition of Pdo into a vinyl epoxide (Scheme 9-23) [44]. In this case, however, the addition of an external base as well as of a proton source are necessary in order to generate the nucleophilic entity and the required palladium hydride catalyst, respectively. 4-Dimethylaminopyridine (4-DMAP) and HOAc turned out to be the best combination for this purpose. One may assume that the hydroacetate formed exerts a bifunctional catalysis and simultaneously acts as an effective template that shapes the conformation of the cyclization precursor. This interpretation is particularly tempting as such reactions proceed smoothly even at rather high concentrations. A straightforward synthesis of the 10-membered product 44, a promising endopeptidase inhibitor, illustrates the convenience of this elegant new methodology (Scheme 9-24) [44,45].

268

9 Ternplated or Not Ternplated, That is the Question

H-Nv B-B, HX

5 5 :denotes a currpound with 2 basic sites

Scheme 9-23

Pd(0) cat., 4-DMAPHOAc

86%

A

42

(E = COOEt)

43

44

t“

Ho

Scheme 9-24

9.7 Summary Although the few examples compiled in this review provide by no means a comprehensive picture, their analysis highlights a few general notions concerning templated ring closure reactions. They show beyond doubt that a “template effect” is not a uniform phenomenon and no simplistic global picture can be drawn. The effect may be thermody-

9.8 Experimentul Procediires

269

namic or kinetic in nature and may derive from pronounced chemical affinities, from ion pairing and/or electrostatic attraction of the reacting sites, from coordination induced proximity, from the polarizability of a metal cation or from a specific coordination geornetry, etc. Moreover, it can be rather difficult to distinguish between a “template effect” and other yet more conventional incentives for ring closure. This is particularly true if the substrate contains structural elements that favor cyclization over competing intermolecular reactions (e.g., rigid backbones, multiple chiral centers affecting its conformation, strong internal hydrogen bonds, gem-dimethyl groups) [46] or if ring closure is a priori kinetically highly favorable. Therefore a less prolific use of the terminology “template” seems appropriate which should always be based on a set of appropriate control experiments ruling out more trivial arguments.

9.8 Experimental Procedures 9.8.1 Synthesis of 15,16-Diphenyl-1,4,7,lO-tetraoxa(10.2)[20]paracyclophan-Sene (14, Scheme 9-8) by an Intramolecular McMurry Coupling under “Salt Free” Conditions [19] A suspension of commercial titanium powder (325-mesh) (2.06 g, 43 mmol) in DME and chlorotrimethylsilane (TMSCl) (6 mL) was refluxed for 48 h under Ar. A solution of

diketone 11 (298 mg, 0.584 mmol) in DME (8 mL) was added at once and reflux was continued until TLC showed complete conversion of the substrate (ca. 8 h). The slurry was cooled to ambient temperature, diluted with THF (20 mL), and filtered through a pad of silica, the insoluble residues were washed with THF (20 mL in several portions), the combined filtrates were evaporated, and the crude product was purified by flash chromatography (silica, hexaneslethyl acetate = 2 : 1) to afford product 15 as colorless, hygroscopic crystals (158 mg, 57%), m.p. (DSC) = 184.6 “C.

9.8.2 Synthesis of Oxacyclohexadec-ll-en-2-one (22, Scheme 9-14) via RCM [32] A solution of diene 21 (298 mg, 1.12 mmol) in CH2C1, (100 mL) was slowly added via a dropping funnel to a solution of (PCy3)2Cl,Ru=CHCH=CPh, (40 mg, 4 mot%) in CH2C12(100 mL) under Ar. After being stirred for 30 h at ambient temperature, the solvent was evaporated and the crude product purified by flash chromatography (silica, hexaneslethyl acetate = 100 : 1) affording lactone 22 (EIZ=46 : 54) as a colorless syrup (219 mg, 79%).

9.8.3 Palladium-catalyzedAlkenyl Epoxide Cyclization: Synthesis of Macrocycle 39 (Scheme 9-22) [42] To a refluxing solution of Pd(PPh,), (23 mg, 0.02 mmol) and dppe (16 mg, 0.04 mmol) in THF (100 mL) was added a solution of substrate 38 (108 mg, 0.20 mmol) in THF

270

9 Templated o r Not Templated, That is the Question

(40 mL) dropwise over a period of 6 h. The reaction mixture was refluxed for an additional 10 h, cooled to ambient temperature, and extracted with H,O/ethyl acetate, and the organic layer was dried over Na,S04. After evaporation of the solvent, the crude product was purified by flash chromatography (SO,, hexanedethyl acetate = 3 :1) affording product 39 (92 mg, 85%, mixture of diastereoisomers) as a pale yellow foam.

References [ I ] (a) E. J. Corey, K. C. Nicolaou, L. S. Melvin, J. Am. Chem. SOC. 1975, 97, 653-654 and 654-655; (b) K. C. Nicolaou, Tetrahedron 1977,33,683-710. [2] The first proposal that a template effect is operative in such cases has been made by Greene, although a perusal of Pederson’s original paper suggests that its seminal crown ether synthesis also relies on this effect. Cf.: (a) C. J. Pedersen, J. Am. Chem. SOC. 1967,89,7017-7036; (b) R. N. Greene, Tetrahedron Lett. 1972, 1793-1796. For a comprehensive treatise of the template effect in crown ether syntheses see [4] and literature cited therein. [3) (a) P. W. Jolly, G. Wilke, The Organic Chemistry of Nickel, Vol. 2, Academic Press, New York, 1975; (b) G. Wilke, Angew. Chem. 1988,100, 189-211; Angew. Chem., Int. Ed Engl. 1988,27, 185-206. [4] (a) For a recent comprehensive treatise of templated syntheses of macrocyclic polyethers and related host compounds see: Template Synthesis (N. V. Gerbeleu, V. B. Arion, J. Burgess, Eds.), Wiley- VCH, Weinheim, 1999 and literature cited therein. (b) See also: R. Hoss, F. Vogtle, Angew. Chem. 1994,106,389-398; Angew. Chem. Int. Ed. Engl. 1994,33,375-384. [ 5 ] Reviews: (a) G. Rousseau, Tetrahedron 1995, 51, 2777-2849; (b) N. A. Petasis, M. A. Patane, Tetrahedron 1992,48, 5757-5821; (c) G. A. Molander, Acc. Chem. Res. 1998, 31, 603 -609. 161 A. Fiirstner, H. Szillat, B. Gabor, R. Mynott, J. Am. Chem. SOC.1998, 120,8305-8314. [7] S. Ma, E. Negishi, J. Am. Chem. SOC.1995, 117,6345-6359. [8] For general discussions of the effect of ring size on cyclization see: (a) E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic Compounds, Wiley, New York, 1994; (b) J. E. Baldwin, J. Chem. SOC.,Chem. Commun. 1976,734-736 and 738-741. [9] For general reviews on macrocycle syntheses see: (a) P. h o p s , N. Sendhoff, H. B. Mekelburger, F. Vogtle, Top. Cur,: Chem. 1992, 161, 1-36; (b) Q. Meng, M. Hesse, Top. Cur,: Chem. 1992, 161, 107-176; (c) M. Bartra, F. Urpi, J. Vilarrasa in Recent Progress in the Chemical Synthesis ofAntibiotics and Related Microbial Products, Vol.2 (Lukacs, G., Ed.), Springer, Berlin, 1993, pp. 1-55; (d) C. J. Roxburgh, Tetrahedron 1995, 51, 9767-9822; (e)H. Stach, M. Hesse, Tetrahedron 1988,44, 1573-1590; (f)M. A. Tius, Chem. Rev. 1988, 88,719-732. [lo] For recent reviews see: (a) A. Fiirstner, B. Bogdanovic, Angew. Chem. 1996, 108, 25832609; Angew. Chem.,Int. Ed. Engl. 1996,35,2442-2469; (b) A. Fiirstner in Transition Metals for Organic Synthesis (M. Beller, C. Bolm, Eds.), Wiley-VCH, Weinheim, 1998, pp. 38 1-401; (c) T. Lectka in Active Metals. Preparation, Characterization, Applications (A. Fiirstner, Ed.), VCH, Weinheim, 1996, pp. 85- 131; (d) J. E. McMuny, Chem. Rev. 1989,89, 1513- 1524; (e) M. Ephritikhine, Chern. Commun. 1998,2549-2554. [ l l ] J. E. McMurry, M. P. Fleming, K. L. Kees, L. R. Krepski, J. Org. Chem. 1978, 43, 32553266. [12] A. L. Baumstark, C. J. McCloskey, K. E. Witt, J. Org. Chem. 1978,43,3609-3611.

References

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[13] J. P. Schaefer, J. J. Bloomfield, Org. React. 1967, 15, 1-203. [ 141 Reviews: (a) J. J. Bloomfield, D. C. Owsley, J. M. Nelke, Org. React. 1976,23,259-403; (b) K. Ruhlmann, Synthesis 1971,236-253; (c) K. T. Finley, Chern. Rev. 1964,6#,573-589 and

literature cited.

[ 151 (a) K. Ziegler in Houben- Weyl,Methoden der Organischen Chemie, Mil. 4(2), Thieme, Stutt-

gart, 1955, pp. 729-822; (b) P. Ruggli, Liebigs Ann. Chem. 1912,392,92-100; (c) Review: L. Rossa, F. Vogtle, Top. Curr Chem. 1983, 113, 1-86. [16] It should be emphasized that the expression “high dilution” is ambiguous terminology, although quite frequently used by preparative chemists to denote a slow feeding rate of the substrate into the reaction mixture (e.g., via syringe pumps). A more accurate description of cyclization reactions refers to the “effective molarity parameter (EM)”, which is a quantitative measure of the propensity of a given substrate to cyclization. For an in-depth treatise see the following reference and literature cited therein: L. Mandolini, Adv. Phys. Org. Chem. 1986, 22, 1 - 11I ; see also Chapter I. [I71 A. Fiirstner, A. Hupperts, J. Am. Chem. Soc. 1995, 117,4468-4475. [ 181 For a study on the morphological basis for the activation of commercial titanium by chlorosilanes see: A. Furstner, B. Tesche, Chem. Mater. 1998, 10, 1968- 1973. [19] (a) A. Fiirstner, G. Seidel, C. Kopiske, C. Kriiger, R. Mynott, Liebigs Ann. 1996, 655-662; (b) for an investigation on the structure and ion-pairing behavior of these crownophanes see: F. Barbosa, V. PCron, G. Gescheidt, A. Fiirstner, J. Org. Chem. 1998, 63, 8806-8814. [20] M. D. Ferguson, J. A. Butcher, Tetrahedron Lett. 1993, 3719-3722. [21] It has long been assumed that metallic Ti is formed on treatment of TiCl, or TiCl, with reducing agents such as Li, K, Mg, Zn, LiAlH,, etc. and that the different reactivity of individual samples stems from differences in the texture and size of the particles. Recent investigations, however, prove beyond doubt that this simplified view is incorrect and that low-valent rather than metallic titanium samples are formed which differ in their composition and reactivity depending on their mode of preparation. For leading references see: (a) L. E. Aleandri, S. Becke, B. Bogdanovic, D. J. Jones, J. Rozikre, J. Organomet. Chem. 1994,472,97-112; (b) L. E. Aleandri, B. Bogdanovic, A. Gaidies, D. J. Jones, S. Liao, A. Michalowicz, J. Rozibe, A. Schott, J. Organomet. Chem. 1993, 459, 87-93; (c) B. Bogdanovic, A. Bolte, J. Organomet. Chem. 1995,502, 109-121. [22] J. E. McMurry, M. G. Silvestri, M. P. Fleming, T. Hoz, M. W. Grayston, J. Org. Chem. 1978, 43,3249-3254. [23] (a) A. Fiirstner, Synthesis 1989, 571 -590; (b) A. Furstner, in Organozinc Reagents. A Practical Approach (P. Knochel, P. Jones, Eds.), Oxford University Press, Oxford, 1999, pp. 287305; (c) M. W. Rathke, in Comprehensive Organic Synthesis, Vol.2 (B. M. Trost, I. Fleming, Eds.), Pergamon, Oxford, 1991, pp. 277-299; (d) M. W. Rathke, Org. React. 1975, 22, 423-460. [24] K. Maruoka, S. Hashimoto, Y. Kitagawa, H. Yamamoto, H. Nozaki, J. Am. Chem. Soc. 1977, 99,7705-7707. [25] (a) T. Tabuchi, K. Kawamura, J. Inanaga, M. Yamaguchi, Tetrahedron Lett. 1986,27, 38893890; (b) J. Inanaga, Y. Yokoyama, Y. Handa, M. Yamaguchi, Tetrahedron Lett. 1991, 32, 6371-6374. [26] T. Moriya, Y. Handa, J. Inanaga, M. Yamaguchi Tetrahedron Lett. 1988,29, 6947-6948. [27] S. Inoue, Y. Iwabuchi, H. Irie, S. Hatakeyama, Synlett 1998,735-736. [28] (a) T. Mukaiyama, I. Shiina, H. Iwadare, M. Saitoh, T. Nishimura, N. Ohkawa, H. Sakoh, K. Nishimura, Y. Tani, M. Hasegawa, K. Yamada, K. Saitoh, Chem. Eur J. 1999,5, 121- 161; (b) See also: I. Shiina, K. Uoto, N. Mori, T. Kosugi, T. Mukaiyama, Chem. Lett. 1995,181- 182.

272

9 Templuted o r Not Templated, That is the Question

[29] For general reviews on RCM see: (a) R. H. Grubbs, S. Chang, Tetrahedron 1998,54,44134450; (b) A. Furstner, Top. Organomet. Chem. 1998, I , 37-72; (c) M. Schuster, S. Blechert, Angew. Chem. 1997, 109, 2125-2144;Angew. Chem., In?. Ed. Engl. 1997,36,2037-2056; (d) A. Furstner, Top. Catal. 1997,4, 285-299; (e) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc. Chem. Res. 1995,28,446-452. [30] (a) Mechanistic discussion of metathesis in general: J. L. Herisson, Y. Chauvin, Makromol. Chem. 1970,141, 161- 176; (b) K. J. Ivin, J. C. Mol, OlefnMetathesis andMetathesis Polymerization, 2nd edn., Academic Press, New York, 1997. [31] This view has been launched, e.g., in [29e]; see also: (a) H.-G. Schmalz,Angew. Chem. 1995, 107, 1981-1984; Angew. Chem., Int. Ed. Engl. 1995,34, 1833-1836; (b) U. Koert, Nachx Chem. Techn. Lab. 1995,43,809-814. [32] (a) A. Furstner, K. Langemann, J. Org. Chem. 1996, 61, 3942-3943; (b) A. Furstner, K. Langemann, Synthesis 1997,792-803. [33] (a) Y.-S. Shon, T. R. Lee, Tetrahedron Lett. 1997,38, 1283- 1286; (b) S. K. Armstrong, B. A. Christie, Tetrahedron Lett. 1996,37,9373-9376; (c) J. L. Mascarenas, A. Rumbo, L. Castedo, J. Org. Chem. 1997,62,8620-8621. [34] (a) Dactylol: A. Furstner, K. Langemann, J. Org. Chem. 1996,61, 8746-8749; (b) Lasiodiplodin: A. Furstner, N. Kindler, Tetrahedron Lett. 1996,37,7005-7008; (c) Jasmin Ketolactone: A. Fiirstner, T. Muller, Synlett 1997, 1010-1012; (d) Epilachnene: see [32b]; (d) Zeranol: A. Fiirstner, G. Seidel, N. Kindler, Tetrahedron, 1999,55, 8215-8230; (e) Tricolorin A: A. Furstner, T. Miiller, J. Org. Chem. 1998, 63, 424-425; (f) Roseophilin: A. Furstner, T. Gastner, H. Weintritt, J. Org. Chem., 1999,64,2361-2366; (g) Tricolorin G: A. Furstner, T. Muller, J. Am. Chem. Soc, in press; (h) Cyclononylprodigiosin:A. Fiirstner, J. Grabowski, in preparation. [35] For leading references on other RCM-based macrocyclization reactions see: (a) S. J. Miller, H. E. Blackwell, R. H. Grubbs, J. Am. Chem. Soc. 1996,1Z8,9606-9614; (b) Z. Yang, Y. He, D. Vourloumis, H. Vallberg, K. C. Nicolaou, Angew. Chem. 1997, 109, 170-173; Angew. Chem., In?. Ed. Engl. 1997,36, 166- 168; (c) K. C. Nicolaou, Y. He, D. Vourloumis, H. Vallberg, Z. Yang, Angew. Chem. 1996,108,2554-2556; Angew. Chem.,In?. Ed. Engl. 1996,35, 2399-2401; (d) D. Schinzer, A. Limberg, A. Bauer, 0. M. Bohm, M. Cordes, Angew. Chem. 1997,109,543-544; Angew. Chem., Int. Ed. Engl. 1997,36, 523-524; (e) P. Bertinato, E. J. Sorensen, D. Meng, S. J. Danishefsky, J. Org. Chem. 1996,61,8OOO-8001; (f) Z. Xu, C. W. Johannes, A. F. Houri, D. S. La, D. A. Cogan, G. E. Hofilena, A. H. Hoveyda, J. Am. Chem. SOC.1997, 119, 10302-10316; (g) S. F. Martin, Y. Liao, H.-J. Chen, M. Patzel, M. N. Ramser, Tetrahedron L.ett. 1994,6005-6008; (h) A. K. Ghosh, K. A. Hussain, Tetrahedron Lett. 1998, 1881- 1884; (i) E. Magnier, Y.Langlois, Tetrahedron Lett. 1998,39, 837-840; (i) H. E. Blackwell, R. H. Grubbs, Angew. Chem. 1998, 110, 3469-3472; Angew. Chem., In?. Ed. Engl. 1998,37, 3281-3284; (k) K. Arakawa, T. Eguchi, K. Kakinuma, J. Org. Chem. 1998, 63,4741-4745; (1) T. Nishioka, Y. Iwabuchi, H. Irie, S. Hatakeyama, TetrahedronLett. 1998, 39,5597-5600; (m) W. P.D. Goldring, A. S. Hodder, L. Weiler, Tetrahedron Lett. 1998,39, 4955-4958; (n) H. El Sukkari, J. P. Gesson, B. Renoux, Tetrahedron Lett. 1998,39,40434046; (0)R. M. Williams, J. Liu, J. Org. Chem. 1998, 63, 2130-2132; (p) Y,Gao, F? LaneBell, J. C. Vederas, J. Org. Chem. 1998,63,2133-2143. [36] A. Furstner, K. Langemann, J. Am. Chem. Soc. 1997,119,9130-9136. [37] Elucidation of the correct structure: (a) W. L. Meyer, W. B. Schweizer, A. K. Beck, W. Scheifele, D. Seebach, S. L. Schreiber, S. E. Kelly, Helv. Chim. Acta 1987, 70,281-291. For previous syntheses see: (b) G. Adam, R. Zibuck, D. Seebach, J. Am. Chem. SOC. 1987, 109, 6176-6177; (c) S. L. Schreiber, S. E. Kelly, J. A. Porco, T. Sammakia, E. M. Suh, J. Am.

Re ferericrs

[38]

[39]

[40] [41] [42] [43] [44] [45] [46]

273

Chem. SOC. 1988, 110, 6210-6218; (d) D. Seebach, G. Adam, R. Zibuck, W. Simon. M. Rouilly, W. L. Meyer, J. F. Hinton, T. A. Privett, G. E. Templeton, D. K. Heiny, U. Gisi. H. Binder, Liebigs Ann. 1989, 1233- 1240; (e) N. R. Curtis, A. B. Holmes, M. G. Looney, N. D. Pearson, G. C. Slim, Tetrahedron Lett. 1991,32,537-540; (9 S . Takano, Y. Shimazaki. M. Takahashi, K. Ogasawara, J. Chem. Soc. Chem. Commun. 1988, 1004- 1005; (8) M. Matsushita, M. Yoshida, Y. Zhang, M. Miyashita, H. Irie, T. Ueno, T. Tsurushima, Cbem. Pharin. Bull. 1992,40, 524-527. For the development of the intermolecular version of this reaction and applications thereof see: (a) B. M. Trost, G. A. Molander, J. Am. Chem. Soc. 1981, 103, 5969-5972; (b) J. Tsuji. H. Kataoka, Y. Kobayashi, Tetrahedron Lett. 1981, 22, 2575-2578; (c) 8.M. Trost, M. A. Ceschi, B. Konig, Angew. Chem. 1997,109, 1562- 1564; Angew. Chem., Int. Ed. Engl. 1997, 36, 1486- 1489. For applications to cyclization reactions see: (a) B. M. Trost, R. W. Warner, J . Am. CIzem. Soc. 1982, 104,6112-6114; (b) B. M. Trost, R. W. Warner, J. Am. Chem. SOL.. 1983, 105, 5940-5942; (c) A. S. Kende, I. Kaldor, R. Aslanian, J. Am. Chem. SOL..1988, 110. 62656266; (d) B. M. Trost, J. T. Hane, P. Metz, Tetrahedron h t t . 1986,27,5695-5698; (e) B. M. Trost, T. S. Scanlan, J. Am. Chem. SOC.1989,111,4988-4990; (9 B. M. Trost, B. A. Vos, C. M. Brzezowski, D. P. Martina, Tetrahedron Lett. 1992,33,717-720. Reviews: (a) B. M. Trost, Angew. Chem. 1989, 101, 1199-1219; Angew. Cbem., Int. Ed. Engl. 1989, 28, 1173-1192; (b) J. Tsuji, Palladium Reagents and Cutaljsts, Wiley, New York, 1995. For a discussion of the “pseudodilution effect” reached with polymer-bound Pdo see [39a, fl and references cited therein. (a) A. Fiirstner,. H. Weintritt, J. Am. Chem. SOC. 1998, 120, 2817-2825; (b) A. Fiirstner, H. Weintritt, J. Am. Chem. SOC.1W,119,2944-2945. For the metathesis route to roseophilin see [34fj; for yet another RCM approach to this target see: s. H. Kim, I. Figueroa, P. L. Fuchs, Tetrahedron Lett. 1997,38,2601-2604. B. M. Trost, P.-Y. Michellys, V. J. Gerusz, Angew. Chem. 1997, 109, 1837-1839; Angew. Chem., Int. Ed. Engl. 1997,36, 1750-1753. For related methodology see inter alia. Y. Yamamoto, M. Al-Masum, N. Asao, J. Am. Cbenz. SOC.1994,116,6019-6020. For comprehensive treatises on conformational effects see: (a) R. Gottlich, B. C. Kahrs, J. Kriiger, R. W. Hoffmann Chem. Commun. 1997,247-257 and literature cited therein; (b) see also [Sa].

Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

10 Use of the Temporary Connection in Organic Synthesis Liam R. Cox, Steven V Ley

10.1 Introduction Classical methods of bond formation invariably involve intermolecular processes. A number of problems, however, are associated with this type of bond-forming event. These often include unacceptably low levels of regio- and stereoselectivity. One approach which helps to circumvent some of these problems is to temporarily intramolecularize [ 11 a reaction. This exploits the advantages associated with intramolecular transformations, while still affording an end-product which is the net result of the desired intermolecular process. The advantages of intra- over intermolecular transformations are manifold. By increasing the proximity between reacting centers, activation entropy is reduced. This facilitates bond formation, often allowing the intramolecular reaction to proceed under milder conditions than its intermolecular counterpart. Intramolecularization also affects the kinetics of the process, which often equates to an increase in the rate of the desired reaction relative to reagent-consuming side reactions: in kinetically controlled reactions, this improves the yield of the required product at the expense of troublesome side products. By bringing together the reacting centers about a uniting template, additional conformational constraints are imposed on the reacting system resulting in more defined transition states (T. S . ) and concomitant increased levels of regio- and stereoselectivity in the end-products. One of the more successful methods of achieving intramolecularization is to use the socalled temporary connection [2]. Using this concept, the reactants are covalently attached to one another through an atom or series of atoms, which function as a disposable tether. For this approach to be successful, a number of design criteria need to be satisfied. Introduction of the tether must be facile. It should be of sufficient length and flexibility so as not to hinder reaction - by increasing strain in the T. S. - but it should not be so long that unfavorable entropic factors become dominant once more. Similarly it is also undesirable for the tether to be so short and rigid that approach of the reacting centers is hindered, or causes excessive buildup of strain in the T. S. The tether should also be appropriately designed to act as a template about which the reacting groups are pre-organized to react through a defined T. S . This can lead to high levels of stereo- and regiocontrol which may enhance, or in some cases reverse, the inherent controlling bias in the corresponding intermolecular reaction. Upon completion of the reaction, the tether should be readily removed or allow further manipulation in subsequent transformations (Figure 10-1).

10 Use of the Temporary Connection in Organic Synthesis

276 n

Y

+

FG’

F G ~

zu

(r

n w x tether formation

/w z‘

FG~

W

FG’ and FG‘

+

release product from tether

*

Figure 10-1 Use of the temporary connection in bond formation.

Incorporating asymmetry into the tether also creates the potential for effecting stereochemical transcription where stereochemical information can be relayed in a defined manner from existing sites to the newly generated stereogenic center(s). This chapter will concentrate on examples of templated synthesis where the template takes the form of a temporary, covalent tether. The intermediate molecule containing both reacting species is in all cases isolabk (or potentially so). This distinguishes this intra molecularization approach from substrate-directed stereoselective synthesis. In this case, the template, most frequently a metal, is used in a much more transient sense allowing the potential for developing catalytic systems, which is obviously not possible using a covalently bound template. The guiding concept of pre-organizing reagents by covalent attachment to a template is quite general. It has been successfully applied to a wide range of important reaction types using an array of tethers. This alone bears testimony to the utility of this approach in facilitating reaction and providing regio- and stereocontrol. This chapter will not provide an exhaustive list of tethered reaction systems [3]. Instead, we have chosen to concentrate on highlighting the variety of tethers and transformations which have benefited from the concept of using a temporary connection. Emphasis will be laid on areas where this tethering approach has provided unique advantages over the analogous intermolecular reaction. The examples of temporary tethering strategies discussed in Section 10.2 all involve cycloaddition reactions, which is where this approach to controlling both regio- and stereoselectivity has found most success. The rest of this chapter will endeavor to illustrate the diversity of reaction types which have also benefited from the use of a temporary connection to bind together reacting fragments. In most cases, the reactions will involve tethers which have been already described. Consequently their preparation and removal will not be discussed in detail; rather we will concentrate on highlighting the advantages of using the tethering approach for achieving stereo- and regiocontrol over the analogous intermolecular systems.

10.2 Cq'cloudditionReactions

277

10.2 Cycloaddition Reactions 10.2.1 [4 + 21 The Diels-Alder Reaction The reaction between a 4 x-(diene) and a 2 n-system (dienophile), otherwise known as the Diels-Alder reaction, is undoubtedly one of the most important reactions for the construction of six-membered rings. Since up to four adjacent stereogenic centers can be generated in a single step, this reaction has become particularly valuable in synthesis. A wide variety of systems have been investigated and in the case of polarized dieneklienophiles, excellent levels of stereo- and regiocontrol can be observed. However levels of regiocontrol, and sometimes stereocontrol, drop significantly in less polarized systems. rendering the reaction less useful. By joining the diene and dienophile together through a tether, the intramolecular variant provides an entry into polycyclic systems [4].Significantly, the intramolecular Diels- Alder (IMDA) reaction differs from its intermolecular counterpart in that levels of stereocontrol, and especially regiocontrol, are usually appreciably higher, even for non-polarized systems. The tether linking the reacting n-systems increases steric and geometrical constraints by minimizing, for example, transannular and A'*3-interactions. This serves to reduce the number of possible low-energy T. S.s, accounting for the improvements in both regio- and stereocontrol. Two variants of the IMDA reaction may be recognized. In the first, the so-called Type I IMDA, the dienophile is joined to a terminal position of the diene, producing relatively strain-free bicyclic products. In the Type I1 IMDA [5], the dienophile is linked to an internal position of the diene. Cyclization in this case results in the formation of a more strained system containing a bridgehead double bond (Figure 10-2).

Figure 10-2 The two variants of the IMDA.

If the all-carbon tether is replaced by a connection which may be removed after reaction, then the IMDA can be used to construct six-membered rings with high levels of stereo- and regiocontrol, which would otherwise be impossible or very difficult to prepare using the analogous intermolecular reaction. A wide variety of tethering systems have been examined and proved to be successful in the formation of highly functionalized cyclohexanes.

278

I0 Use of the Ternmrurv Connection in Ormnic Svnthesis

10.2.1.1 Type I IMDA reactions Silicon tethers Silyl acetals Silyl acetals are attractive tethering agents owing to the ease with which they may be removed after reaction. Craig and co-workers were the first to report the use of such a connecting group in an IMDA reaction [6]. Triene 1 was prepared by the addition of equimolar amounts of dienol 2 and hydroxy enoate 3 to a cooled solution of Ph2SiC12 and Et,N in CH2C12(Scheme 10-1). The desired mixed silyl acetal 1 was isolated in moderate yield after purification by column chromatography on Horisil@,together with small amounts of the symmetrical acetals resulting from double addition of each starting alcohol. Attempted formation of the dimethylsilyl analog proved problematic owing to its greatly increased sensitivity towards hydrolysis.

'. 'OH

5

HCI. MeOH.

4

Scheme 10-1 Thermolysis of silyl acetal 1 provides a single IMDA product.

Despite the moderate yields in preparing the starting triene, the subsequent IMDA reaction proved very successful. Thermolysis of 1 in toluene at 160°C for 168 h afforded a 13 :87 mixture of the starting material and a singk, bicyclic product 4 (Scheme 10-1). Cyclization was completely regio- and stereoselective and may be accounted for by invoking an ex0 T. S. (Figure 10-3). Cleavage of the silyl tether was effected by acidic methanolysis and provided hydroxylactone 5 as a single stereoisomer. The structure of 5 was confirmed by X-ray crystallographic analysis. The importance of the tether in enabling such high stereo- and regiocontrol was further exemplified upon investigation of the analogous intermolecular reaction [6a, d]. Exposing silyl ethers 6 (diene) and 7 (dienophile) to similar reaction conditions provided a mixture of all four possible regio- and stereoisomers in the ratio 3 :2 :2 :1 (Scheme 10-2).

10.2 Cycloaddition Rractiori.~

279

Ph

1

Figure 10-3 Triene 1 reacts through an a

Me0

x 0

T. S.

OSiPh,Me

,,,,OSiPhzMe

J - LOSiPhzMe 6

+

-

MePhzSiO&OMe

-

OMe

PhMe, 155"C, 145h

0

,,,.q;i?Me

7

MePh2SiO'

MePhpSiOy

Scheme 10-2 Intermolecular reaction of 6 and 7 is neither stereo- nor regioselective.

Perhaps the greatest drawback with this tethering approach is the relatively poor yield in the formation of the triene IMDA precursor 1, although the reaction was not optimized. Fortin and co-workers have reported an improved procedure for the efficient formation of unsymmetrical di-tert-butylsilyl acetals using 'Bu,Si(CI)OTf, which is readily prepared from the corresponding chlorosilane [7]. Successive incorporation of the dienophile and diene is possible by exploiting the different reactivity of silyl tritlates and chlorides towards nucleophilic substitution (Scheme 10-3).

Qu.si ,OTf

'Bu

/

\

C'

H O A C O Z E t

PY, THF,

*

-20°C t o o "C. 2h, 85%

lBU.Si.O&COzEt

n-

d

THF, DMF, 0 "C, 4h

-si,O&COzEt

OTMS.

MeLi,

'BU

*

tBL

\o

I\

Scheme 10-3 Successive displacement of triflate and chloride allows preparation of mixed ditert-butylsilyl acetals.

Thermolysis of triene 8 in xylene at 160- 180 "C afforded a 9 : 1 mixture of cyclization products in excellent yield, with the major product 9 resulting from an endo T. S. Regiocontrol, however, was complete with the formation of exclusively the "head to tail" isomer (Figure 10-4).

10 Use ofthe Temporary Connection in Organic Synthesis

280

endo T.S. favored

CO*Et major product 9

0

disfavored

Figure 10-4 Steric interactions between the tether and diene are responsible for the observed stereoselectivity.

This result provides a good example in which the presence of the tether reverses the inherent regiochemical bias of the diene/dienophile system. Both the diene and dienophile are strongly polarized systems. As a result, the corresponding intermolecular reaction proceeds with excellent regiocontrol to afford exclusively the “head to head” isomer as a roughly 1 : 1 mixture of endo and ex0 isomers [7].The tether not only exerts a complete regiochemical reversal, but also improves the level of stereoselectivity. Steric interactions between one of the bulky ‘Bu groups in the tether and the diene account for the adoption of an endo T. S. (Figure 10-4). One of the best tests for any synthetic methodology is in its application to the preparation of biologically important compounds. Posner et al. recently reported the use of a silyl acetal tether in an IMDA reaction for the preparation of the 2-fluoroalkyl analog 10 of 1,25-dihydroxyvitamin D, 11 (Figure 10-5) 181. A Lewis acid-promoted, IMDA cycloaddition between an electron-poor pyrone and an electron-rich silyl enol ether was used to prepare the A ring. The requisite tnene 12 was synthesized from alcohol 13 and chlorodiisopropylsilyl enol ether 14. Subsequent ZnBr,-promoted cyclization of 12 allowed slow conversion to the Diels- Alder adducts 15 and 16 in 46%and 12% yields, respectively (Scheme 10-4).The major, endo adduct 15 was subsequently elaborated into fluoroalkyl-vitamin D, analog 10.

11

1,25-dihydroxyvitarninD3

10 -F

Figure 10-5 Analogs of 1,25-dihydroxyvitamin D, are important biological targets.

10.2 Cycloaddition Reuctions

13

14

1

28 I

12

ZnBrp, 2:l PhMe-EtpO, -10 "C, 10 d

15

I F

46%

16

F'

12%

Scheme 10-4 Cyclization proceeds stereoselectively in a stepwise fashion.

The key feature in this IMDA approach was the incorporation of a stereogenic center into the tether, allowing the possibility to control the absolute stereochemical outcome of the cyclization. The use of (S)-1,3-butanediol in the tether gave the best results - cyclization proceeded with excellent asymmetric induction affording only two ( e m and endo products) out of the possible four 4 3 4 s diastereoisomers. It is also noteworthy that this cyclization must proceed in a stepwise fashion since the starting dienophile has a truns geometry while the products possess a cis substitution pattern at C (4) and C ( 5 ) .

Vinyl and dienyl silyl ethers The use of silyl acetals as tethering groups in the IMDA reaction is often hampered by the relatively poor yields observed in the formation of unsymmetrical systems. However, the preparation of the triene precursors can be facilitated if only one of the nsystems is linked through a silyl ether connection, while its reacting partner is attached directly to the silicon tether [9]. Dialkylvinylsilyl halides are readily prepared, for example, by hydrosilylation of acetylenes; indeed, the most simple dimethyl- and diphenylvinylsilyl chlorides are now commercially available. Substitution of the halide with the appropriate hydroxydiene then generates the desired triene precursor. Vinyl silyl ethers are also much more stable than silyl acetals, especially towards hydrolysis; nevertheless, a number of mild methods are still available for subsequent removal of the tether. Stork et al. prepared the two isomeric vinyl silanes 17 and 18, differing only in the double bond geometry of the dienophile [ 101. Cyclization was readily effected in excel-

10 Use of the Temporary Connection in Organic Svnthesis

282

lent yield on heating a benzene solution for 4-6 h at 80 "C. In both cases, the short length of the connecting tether enforced absolute control of regiochemistry. Cyclization also proceeded with complete stereocontrol through an endo addition mode, as evidenced by the formation of the cis- and trans-fused bicycles 19 and 20 from 18 and 17, respectively (Scheme 10-5).

ClMepSi +co

CO2Et 2E1

SiMe2Ci

EtBN, THF

6

@

SiMe2

.,SiMe2

C02Et

CO2Et

/ \

1 eq. TBAF. 10 eq. 30% H202, 55 "C,2 h

22

1

/ \ 19

20

2 eq. TBAF,

6OoC.4h, DMF

23

1 eq. TBAF. 10 eq. 30% H202, 55 "C, 2 h

21

Scheme 10-5 A short tether ensures complete regio- and stereocontrol with vinyl silyl ethers Subsequent tether cleavage is also readily achieved.

Removal of the tether was realized in two ways. Oxidative cleavage of an activated C-Si bond has been shown to proceed with retention of configuration [ 111. Thus treating 19 and 20 with 1 equiv of TBAF and a 30% solution of H,02 in DMF at 55 "C for 2 h afforded the diastereoisomeric diols 21 and 22, respectively, both in 80% yield. Alternatively hydrodesilylation could be achieved using 2 equiv of TBAF in DMF at 60 "C for 4 h. In the case of the cis-fused, bicyclic Diels-Alder adduct 19, the basic conditions of

10.2 Cyclouddition Reactions

283

the reaction led to complete epimerization of the ester substituent onto the less hindered convex face, and the isolation of exclusively alcohol 23 (Scheme 10-5). Sieburth and Fensterbank have studied the effect of tether length on the efficiency of vinyl silyl ether IMDA reactions [ 12al. Trienes with tethers of three or four atoms reacted with equally high efficiency providing good yields of the TMS-substituted alcohols upon workup with MeLi (Scheme 10-6). Extending the tether length by one additional atom, however, resulted in a much slower reaction, presumably owing to entropic factors, and after 20 h at 190 “C appreciable quantities of the triene starting material remained (Scheme 10-6).

i) PhMe, 20 h, 190°C R

R = Me, n = 1

2:l (68%)

R = H, n = 2

1:l (72%)

R = ti,n = 3

ratio not determined (25%)

Scheme 10-6 Effect of tether length on the efficiency of IMDA reactions.

In the cases of dimethylsilyl IMDA precursors, the exolendo selectivity was poor. However, this ratio could be readily and quite dramatically influenced by varying the alkyl substituents on the silicon template [ 121. Thus with dienol24, tether formation with dimethylvinylsilyl chloride and subsequent IMDA reaction afforded a 4 : 1 mixture of exo/endo products (Scheme 10-7).The ratio could be further improved to 10: 1 by using a diphenylsilyl tether, and when bulky ‘Bu groups were used, a single stereoisomer, resulting from ex0 addition, was observed. This example once more illustrates the potential for tuning the stereoselectivity of the reaction by varying the steric interactions with the tether.

OH

o’si4

PhMe

24

ex0 R=Me

endo

4:1

R = Ph

1o:i

R=’Bu

>20:1

Scheme 10-7 The steric bulk of the dialkylsilyl tether can influence exolendo selectivity.

284

10 Use of the Tempomiy Connection in Organic Synthesis

Dienylsilyl ethers have been less widely investigated in spite of the fact that this tethering pattern provides one of the first examples of a silyl-tethered IMDA reaction [ 13, 141. Tamao, Ito, and Kobayashi demonstrated that 1,7-diynes undergo stereospecific NiO-catalyzedhydrosilylation generating the corresponding 1,2-dialkylidenecyclohexanes possessing a (2)-vinylsilane moiety [ 131. A variety of silanes could be used to effect this transformation, among them (diethy1amino)dimethylsilane. The resulting dienylamino silane 25 allowed further functionalization by nucleophilic displacement of the labile amino functionality with cinnamyl alcohol (Scheme 10-8). Triene 26 then underwent a smooth IMDA reaction on heating a xylene solution at reflux for 40 h. Oxidative cleavage of the C-Si bond afforded diol27 as a single stereo- and regioisomer.

Me 30% H202, KF, KHCO-.

-

THF-MeOH, 50 "C, 18 h

-

1

Ph-OH

xylene, reflux,

40 h

27

75% (from 25)

26

6h

Scheme 10-8 Dienylsilyl ethers can also be used in IMDA reactions.

Acetal tethers The use of an acetal to tether the diene and dienophile has been investigated by Craig and co-workers [ 151. Preparation of the unsymmetrical acetal precursor was best achieved via the corresponding enol ether. For example, the isopropylidene-linked triene 28 was synthesized in two steps from acetate 29. Tebbe methylenation of 29 afforded enol ether 30,which was used directly in a Pd"-catalyzed addition of the dienophile 3 to form 28 (acid-catalyzed addition with pTSA proved inferior). Thermolysis of 28 in toluene at 165 "C allowed a remarkably facile and completely regiospecific cyclization to take place. Acidic methanolysis of the Diels-Alder adducts resulted in cleavage of the tether and isolation of a 2.7:l mixture of lactones 31 and 32 in 72% yield (Scheme 10-9). The reactivity of triene 28 was greatly increased compared to the analog bearing a single methyl group in the acetal tether, which required 27 h for complete reaction [14]. This may be attributed to the greater degree of alkyl substitution at the acetal center reducing the population of unreactive, distal conformers which experience unfavorable non-bonding interactions between the diene and/or dienophile and the additional methyl group.

29

30 I)

PhMe, 165 "C, 2.5 h

ii) HCI. MeOH

Scheme 10-9 Acetal tethers facilitate Diels-Alder cyclization.

31

I

2.7:l

20

32

72%

Comparison with the analogous silyl acetal-tethered systems also reveals a number of interesting features. The Diels-Alder precursors (e.g., 28) linked through a carbonacetal tether are appreciably more reactive than the analogous silyl acetals (vide supra). This is most probably a result of the shorter C-0 bond length (1.43 & . compared with 1.64 A for Si-0) increasing the local concentration of the dienophile at the reacting diene. On the downside, the use of an acetal tether results in much poorer stereocontrol when compared with the almost complete ex0 selectivity observed with the corresponding silyl acetals: the reduced length of the carbon acetal tether provides a more compact T. S., in which steric interactions between the exo diene and dienophile methylene group are increased, disfavoring this addition mode [ 151. Boeckman et al. used an acetal tether in a racemic synthesis of the cyclohexene subunit of tetronolide 33 [16]. Although it had previously been recognized that a Diels-Alder strategy could provide rapid entry into this highly functionalized six-membered ring, some of the earlier reported intermolecular reactions suffered from relatively poor reactivity and regio- and stereocontrol [ 171. It was anticipated that an intramolecular variant would overcome some of these problems (Scheme 10-10). Formation of the acetal-tethered triene 34 was achieved by selective nucleophilic displacement of the secondary alkyl bromide in 35 with hydroxydiene 36. Subsequent thermolysis at 145 "C for 70 h resulted in completely regiospecific cycloaddition with the formation of two out of the possible four diastereoisomers 37 and 38 in a 2.5-3 : I ratio (Scheme 10- 11). The presence of a stereogenic center in the tether provides the source of stereocontrol -the products derive from ex0 and endo T. S.s in which the bromomethyl group in the tether occupies a pseudo-equatorial position (Scheme 10-1 1 ). Small differences in non-bonding interactions between the tether and pyruvate ester most probably account for the slight exo selectivity. The separated major product was further elaborated, and finally the tether was cleaved under reductive conditions to provide the advanced cyclohexene intermediate 39.

286

10 Use of the Ternporury Connection in Organic Synthesis

Scheme 10-10 An IMDA strategy can be used to prepare the cyclohexene subunit of tetronolide 33.

Et02cf AgOTf, DIPEA, 36

-20 to 25 "C, 88%

Br

Br

35

J

145 "C, 70 h

4H9"co2"u d' C02Et

Br

1

endo

f---

38

13%

-

OTBDPS

OTBDPS

39

Zn(Ag), MeOH, 60 "C, 40 h,

98%

0-0

Br'

-

0-0 Br'

37 38%

Scheme 10-11 Cyclization of 34 proceeds with complete regiocontrol and moderate stereoselectivity.

10.2 Cycloaddition Reactions

287

Ether tethers An early example of an IMDA reaction using an ether linkage to connect the diene and dienophile was provided by Funk et a]. in their preparation of the hexahydronaphthalene fragment of the important hypocholesterolemic agent, compactin 40 (Scheme 10- 12)

&42

compactin 40

Scheme 10-12 An IMDA reaction can be used to prepare the lower half of compactin.

Formation of the requisite triene 41 was readily achieved by alkylation of hydroxydiene 24 with 1-bromobut-2-yne (Scheme 10-13).The stereospecificity of the concerted Diels-Alder reaction required a cis-configured dienophile to react through the sterically less demanding ex0 T. S . to afford the desired product 42. A chemoselective hydroboration/protonolysis sequence on propargylic ether 43 allowed access to the desired cis olefin 41 in good yield. Subsequent thermolysis at 165 "C in toluene afforded a 4 : 1 mixture of stereoisomers with the major product being the desired ex0 isomer 42. Unactivated primary alkyl ethers are rarely used as tethers, owing to the relatively harsh reaction con-

i) Cy2BH. 12 h 4 d, 79%

24

-

SOzPh

TB* /

/

43

steps T t-

78% (2 steps)

M \

-&+&

41

J

165 "C,2 d, PhMe, 69%

TMSI, ~

quinoline,

70%

\\I'

\

\

42 4: 1

Scheme 10-13 Ether-linked triene 41 has been elaborated to the hexahydronaphthalene portion of compactin.

288

10 Use of the Temporury Connection in Organic Synthesis

ditions required for their subsequent cleavage. In this case, however, the use of a more labile ester tether proved problematic in the Diels-Alder step owing to a facile elimination side reaction [ 181. Fortunately the ether tether, which did not suffer this side reaction in the cycloaddition reaction, was readily cleaved regioselectively using TMSI in the presence of quinoline (Scheme 10-13). Craig and co-workers have investigated the use of benzylic and tertiary alkyl ethers as temporary tethers in IMDA reactions [ 191. Both these functionalities are more readily cleaved under a variety of conditions. A convergent and highly flexible approach was used to prepare the triene precursors. Thus treating acetone or benzaldehyde with TMS ethers under TMSOTf activation afforded the corresponding acetals, which were then used in a Sakurai coupling reaction with 5-trimethylsilylpenta-1,3-diene. The two steps were best accomplished in a one-pot process providing excellent yields of the etherlinked trienes (Scheme 10-14).

R' = R2 = Me, 97%

R' = Ph, R2 = H. 98%

Scheme 10-14 Ether-linked trienes have been prepared in a convergent and flexible manner.

Cyclization studies were carried out in sealed tubes in toluene solutions at 165 "C and provided excellent yields of the corresponding bicyclic cycloadducts in 5 -9 h. Reactions of tertiary alkyl ethers showed moderate to complete trans selectivity. This selectivity was observed even for inherently cis-directing systems and may be attributed to the gem-dimethyl group in the ether tether: comparison of the reacting conformations leading to cis- and trans-fused decalins reveals, in the cis case, an unfavorable non-bonding interaction between the axial methyl group and H-C(3) of the diene (Scheme 10-15).

[

inherently Cis-direW substrate

I

trans product favored trans : cis 6:l

total yield 84%

Scheme 10-15 Trienes linked through a tertiary alkyl ether are trans-selective.

10.2 Cyckoaddition Recictioris

2x9

The presence of an additional stereocenter in the ether linkage of PhCHO-derived trienes provides the possibility for additional stereocontrol. Thus thermolysis of triene 44 afforded a 2 : 1 mixture of decalin products 45 and 46 in excellent yield. These arise respectively from endo and exo addition of the diene to the same diastereoface of the dienophile via a T. S. in which the phenyl substituent in the tether is pseudo-equatorially disposed (Scheme 10-16).

2:l 91%

Scheme 10-16 Triene 44 linked through a benzylic ether tether also undergoes a stereoselective IMDA reaction.

As a result of the excellent diastereocontrol observed in these reactions, it was envisaged that the use of chiral ether linkages might impart a degree of absolute stereocontrol on the IMDA reaction [19b]. Preliminary results were encouraging. For example, the menthone-derived triene 47 provided a 10 : 1 mixture of two (out of a possible four) diastereoisomers with proposed structures 48 and 49 in 94%yield (Scheme 10-17). Cleavage of the tethers was achieved in a number of ways affording a variety of products, ripe for further elaboration (Scheme 10-18). C02Me

'P r

ia0-C02Me /

47

~

/

I,

48

'

"Pr

1O:l

49

94%

Scheme 10-17 Asymmetry in the ether linkage can impart absolute stereocontrol on the cycloaddition.

10 Use of the Temporary Connection in Organic Synthesis

290

rp

SOnPh

H

HO$ph

i

Ph 65%

71%

CI

Ph

71%

Scheme 10-18 Cleavage of the ether tethers after cycloaddition.

Boron tethers The use of a boron atom as a covalent template for intramolecularizing the Diels-Alder reaction has been relatively little investigated [20-221. However Narasaka et al. have reported the use of a boronate template to control regio- and stereoselectivity in an IMDA reaction between anthrone 50 and methyl 4-hydroxybut-2-enoate 3 [20a]. Formation of the boronate tether was achieved by simply heating an equimolar mixture of phenylboronic acid with the diene and dienophile at reflux in pyridine with azeotropic removal of water. After 5 h, a single cycloadduct 51 was obtained in 81% yield. The tether was readily removed oxidatively affording the corresponding diol52 in excellent yield (Scheme 10-19). 0

50

3

C02Me

~

52

95%

ph’

51

81%

Scheme 10-19 A boronate tether has been used to control the regio- and stereoselectivity of a Diels-Alder reaction.

10.2 Cricloaddition Reactions

29 1

Although the boronate-tethered triene intermediate was not isolated, its formation can be implied by the lack of any reaction under the same conditions in the absence of PhB(OH),. The tether also enforces a complete reversal in the regioselectivity of the reaction compared with the analogous intermolecular reactions of acrylates with anthrone [23]. The same group also applied boron reagents to trap reactive dienes and used them in a subsequent IMDA reaction [20b]. o-Quinodimethanes are useful dienes since they allow rapid access to the tetralin skeleton. However, they are fairly unstable and only undergo cycloaddition with reactive dienophiles; in the presence of less reactive dienophiles, the diene isomerizes or dimerizes preferentially. It was envisaged that a suitable boron reagent could be used to intercept an ahydroxy-o-quinodimethane and form a mixed boronate with a hydroxyl-containingdienophile. Tether formation would not only ensure a completely regioselective cycloaddition, but would also prevent isomerization of the reactive diene moiety. Thexylborane was found to be a useful source of the boron template. A solution of the borane, cyclobutanol 53 and dienophile 3 in THF was stirred for 1 h to allow tether formation. The solvent was then exchanged for m-xylene and the reaction mixture heated at reflux for 3 h. Cycloadduct 54 was isolated in 59% yield after hydrolytic workup as an unreported mixture of stereoisomers (Scheme 10-20). The opposite regioisomeric product was not observed, indicating the participation of a boron-tethered intermediate. The intermolecular reaction would, once again, be expected to provide the opposite regioisomer to that formed.

53

1

mxylene, reflux, 3h

59%

Scheme 10-20 Linking the benzocyclobutane and dienophile through a boron tether to form 55 allows interception of the reactive diene formed on ring opening for use in a regioselective IMDA reaction.

I0 Use of the Ternnoran, Connection in Orpanic Svnthesis

292

Inspired by these results, Nicolaou et al. used a temporary boronate tether to overcome the undesired regiochemical bias in the intermolecular Diels-Alder reaction of diene 56 and dienophile 57, required for their approach to the C-ring of taxol 58 [21a, b, 241. Thermolysis of a benzene solution of 56 and 57 in the presence of PhB(OH), under dehydrating conditions provided the cycloadduct 59 in 79% yield (77% conversion) after transacetalization of the boron tether with 2,2-dimethylpropane-1,3-diol and intramolecular acyl transfer to the less strained [4.3.0]bicyclic system. This was further elaborated to an advanced intermediate in the ultimately successful synthesis of taxol (Scheme 1021) [21c].

+

fOEt OH 57

PhB(OH)z, PhH, reflux

oQ 56

OH

sndo T.S.

H

1

acyl transfer

0

P h A

58

OPW

Scheme 10-21 Nicolaou et al. used a boron-tethered cycloaddition to construct the C-ring of taxol.

Sulfonate tethers Metz et al. have investigated the use of sulfonates as covalent.tethers in IMDA reactions [25]. The sulfonate group not only acts as a covalent tether, but if directly attached, can also be used to activate the dienophile. Vinyl sulfonyl chloride is readily prepared [26], and nucleophilic displacement of the chloride functionality by a hydroxy-containing diene effects tether formation. Although the triene precursor can be isolated, the sulfonate functionality is hydrolytically sensitive and generally it is more convenient to cany out the IMDA reaction directly. Vinyl sulfonates exhibit high reactivity in Diels-Alder reactions and cyclization sometimes proceeds at or below room temperature. In the case of triene 60,a highly diastereo- and regioselective IMDA reaction occurred within 2-3 h at 0 "C [25b] with the observed ex0 cycloadduct 61 being formed as the thermodynamic product. A two-step oxidative cleavage protocol was employed to effect tether cleavage: a-lithiation of the sultone with "BuLi followed by trapping with 2-methoxy-4,4,5,5tetramethyl- 1,3,2-dioxaborolane generated the corresponding boronate, which was oxi-

10.2 Cyclouddition Reactions

293

datively decomposed with mCPBA affording y-hydroxyketone 62 in excellent yield (Scheme 10-22).The net result of this reaction is a completely regio- and stereoselective. formal [4 + 21 cycloaddition of ketene to a cyclopentadiene.

64%

HO

THF, 0 "C 60

A

S'O 61

/i)

"BuLi, -70 "C

62

Scheme 10-22 A sulfonate tether affords cycloadducts stereo- and regioselectively.

Recently, Winterfeldt and co-workers used a similar strategy as a key step in the preparation of myltaylenol63 [27]. It was envisaged that diene 64, readily prepared in enantiopure form, could be used in an IMDA reaction with a dienophile, temporarily attached via the hydroxy functionality, to incorporate the remaining two stereogenic centers. Tethering the dienophile would control the facial selectivity of the cycloaddition with attack proceeding onto the sterically more hindered, but desired, a-face of the diene. Interestingly, although a number of tethering strategies were investigated, only the sulfonate produced satisfactory results. Treatment of 64 with vinyl sulfonyl chloride proceeded uneventfully affording sulfonate 65 in excellent yield. Subsequent thermolysis in toluene at 110 "C for 20 h ensured complete conversion to cycloadduct 66 in which the predicted a-attack of the diene was realized (Scheme 10-23). An oxidative cleavage strategy was required for further manipulation to the target. However, the sterically very hindered center at the sultone carbon necessitated a modification of the conditions reported by Metz [25b]. After appreciable experimentation it was found that molecular oxygen could be used to trap the lithiated sultone generated using "BuLi at -78 "C [28]. A large excess of the base was crucial for efficient conversion to the desired hydroxyketone 67. This was further elaborated into the first enantioselective synthesis of myltaylenol. Metz et al. have also demonstrated the use of sulfonate tethers in the preparation of the bicyclic sesquiterpene lactone, ivangulin 68 [25f]. The sulfonate derived from vinyl sulfonyl chloride and diene 69 underwent smooth IMDA reaction affording a mixture of ex0 cycloadducts 70 and 71 in a 1 :1.4 ratio. Heating this mixture in toluene at reflux allowed

294

10 Use of the Temporary Connection in Organic Synthesis

equilibration, via a retro Diels-Alder-Diels-Alder process, to an improved ratio of 9.5: 1 in favor of 71, which is thermodynamically favored owing to the equatorially disposed methyl substituent (Scheme 10-24). This major cycloadduct was separated and further elaborated to advanced intermediate 72 in which all three stereogenic centers had been successfully incorporated. This time, cleavage of the sultone was achieved reductively using dissolving-metal conditions, affording tetrasubstituted olefin 73 as the major product, which was readily manipulated into ivangulin 68.

H1, Pd I C, 99% SBuLi (10.4 eq.),

7: 1 73%

OH

67

myltaylenol

63

Scheme 10-23 A sulfonate tether strategy was used in Winterfeldt’s synthesis of myltaylenol. PhMe, reflux. 70 : 71 (1:9.5),

I

69

70

I

atO°C;70:71 (1:1.4)

O

Me0

ivangulin 68

-

7’

?,s$b4e

,L‘. NHdI), o 73

pOEt 72

major double bond isomer (57%)

Scheme 10-24 A reductive cleavage strategy has been used to remove the sultone tether.

10.2 CycloadditionReactions

295

10.2.1.2 Type I1 IMDA reactions The Type I1 variant of the IMDA reaction usually requires more forcing conditions to effect cyclization than its more frequently encountered Type I analog. This is a direct consequence of the higher-energy T. S. associated with the formation of products containing a strained, bridgehead double bond. This intramolecular variant of the DielsAlder reaction has been most intensively studied by Shea and co-workers who have shown that it can be used in a variety of highly regio- and stereocontrolled cyclizations [5, 291. Ester tethers In an early paper, Shea used a readily prepared ester tether to connect the diene and dienophile [29a, 301. The effect of tether length on cyclization was investigated and was shown to be an important criterion for efficient cyclization. Just as in the Type I IMDA reaction, increasing the number of bridging atoms between the diene and dienophile provides a reaction which increasingly resembles the corresponding bimolecular process and the entropic gain from intramolecularization is expected to diminish. However, the strain energy contribution to the enthalpy term is expected to be much more important in the Type I1 IMDA reaction, with a longer tether being expected to reduce strain energy and facilitate cyclization. A series of trienes were prepared [29a]. In the case of a four-atom tether, reaction was not possible, presumably as a result of highly unfavorable non-bonding interactions in the T. S. Increasing the tether length by one atom allowed reaction to proceed: in all cases, thermolysis in xylene at 185 "C afforded a single regioisomeric product in good yield (Scheme 10-25). Cyclization was even more facile in the case of a six-atom bridge, as illustrated by the reduced temperature required for cyclization: thus, thermolysis of triene 74 at 130 "C afforded a 92 :8 ratio of cycloadducts 75 and 76. This is presumably

xylene, w

o

f

l

Z

R

'

R' = H, = H R' = t i , R2 = COZMe R' = C02Me, R2 = H

n=3 74

185 "C, 5-6 h *

R'

q! -

R'

0

n = 1, no reaction, n = 2,40-60 %, single regioisorner

0 75

92:8

76

Scheme 10-25 Ester groups can be used as the temporary connection in Type II IMDA reactions. Tether length affects the facility and regioselectivity of reaction.

I0 Use of the Temvorant Connection in Orpanic Svnthesis

296

a consequence of reduced strain and non-bonding interactions in the T. S . However, while reaction becomes more facile, the increased flexibility of a longer tether diminishes slightly the level of regiocontrol. Isolation of the minor cycloadduct 76 and saponification of the lactone bridge afforded a 1,Cdisubstituted cyclohexene which corresponded to the major product of the analogous intermolecular Diels-Alder reaction. The regiocontrol of 2-alkyl-substituted 1,3-dienes in Diels-Alder cycloadditions is generally low although it usually favors the “para” cycloadduct [31]. Tethering the diene and dienophile therefore not only increases regioselectivity, but also overrides the inherent regiochemical bias of this reaction.

Silicon tethers Shea and co-workers have also investigated the use of silyl ethers and silyl acetals as temporary connecting groups in the Type I1 IMDA reaction [29i, j, I-n]. Moreover, they have demonstrated that efficient stereochemical transcription is possible by incorporating asymmetry into the linker [29 1, m]. An elegant illustration of the power of this methodology for stereo- and regioselective bond construction is their recent synthesis of the adrenalcorticosteroid (+)-adrenosterone 77 [29m]. Their retrosynthesis is outlined in Scheme 10-26.

77

U

80

Scheme 10-26 Shea’s retrosynthesis of adrenosterone incorporating a Qpe I1 IMDA reaction.

The diene precursor 78 is readily accessed in a few steps from the Wieland-Miescher ketone 79, which also provides the A- and B-rings of the steroid skeleton. Furthermore, the presence of an axial methyl group at C(19) (steroid numbering) allows the possibility of controlling the absolute stereochemical outcome of the key cycloaddition used to

10.2 Cycloaddition Reactions

297

install the C-ring. Preparation of the tethered Diels-Alder precursor 80 was achieved in a highly efficient manner (Scheme 10-27): kinetic deprotonation of ketone 78 with KHMDS and subsequent trapping of the enolate with Ph,SiCl, generated the corresponding diphenylchlorosilyl dienol ether. Chloride substitution with glycol ester 81 afforded silyl acetal80. This was used directly, without purification, in the Diels-Alder reaction, from which a 1:lO mixture of diastereoisomers 82 and 83 was isolated in an excellent 90% yield from ketone 78. Cyclization was not only completely regioselective, but both diastereoisomers resulted from an endo mode of addition. However, the major product proved to be that derived from Pattack of the dienophile, so the hoped-for adirecting effect of the C( 19) methyl group was not realized.

i) KHMDS, -78 'C

Ph2CISiO

ii) PhfiiC17. 0 ' C 78

82

1:10

183

81

80

SO?, [from78 (50%conversion in Diels Alder step)]

Scheme 10-27 Triene formation and subsequent IMDA reaction proceeds with high efficiency and selectivity.

A modified tether, incorporating (-)-hydrobenzoin instead of glycol, was readily prepared from ketone 78 as before, anticipating that steric interactions between substituents at these new stereogenic centers and the diphenylsilyl group would rectify the problem of z-facial selectivity in the cycloaddition. Thermolysis of triene 84 at 200 "C in toluene for 18 h afforded a 3 :2 mixture of cyclized products 85 and 86 respectively, in which the major diastereoisomer resulted from the desired a-approach of the dienophile (Scheme 10-28). Subsequent manipulation generated (+)-adrenosterone in a total of only seven steps from enone 78. In Shea's approach to the polyhalogenated cyclohexane 87, derived from a red marine alga, Plocamium sp., a Type I1 IMDA reaction utilizing a disposable (ally1)silyl tether was used as a key step [29n]. The triene cyclization precursor 88 was readily prepared and underwent Diels-Alder reaction in 74% yield with the expected, complete regiocontrol affording exclusively bicycle 89. The rigid, bicyclic framework of the cycloadduct

I0 Use of the Temporary Connection in Organic Synthesis

298

was then exploited to ensure a completely selective exo-syn chlorination of the bridgehead double bond with iodobenzene dichloride, which installed the desired cis relative configuration between chlorine and bromine. An interesting, reductive cleavage strategy was used to remove the tether: treatment of 90 with DIBALH not only effected ester reduction, but also installed the ex0 methylene group by elimination of the bridgehead chloride. Subsequent manipulations provided ready access to the monoterpene 87 (Scheme 10-29). Ph Ph 0

Ph

-

I

PhMe.

C02Me 200 “C, 18h

85

84

desired stereoisomer

32

88

9O?h[from 70 (45% conversion in Diels Alder step)]

Scheme 10-28 A modified tether incorporating asymmetry provides the desired z-facial selectivity.

0 \

k

- s i A o y % 88

-

.

br.,

\si

PhMe,

185”C, 74%

iodobenzene dichlorie 61%

0

o, iS,

I

89

a

O b C I Br

CI

07

--

I

90

DIBALH,

a

05%

CI

‘‘LOH

Br

Scheme 10-29 A Type JI IMDA strategy was used to prepare the terpenoid marine natural product 87.

The work, by the Shea group in particular, exemplifies the power of the temporary connection in Type II IMDA reactions not only for controlling the regiochemical outcome of the cyclization but also for exerting absolute stereocontrol.

10.2 Cvcloaddition Reactions

299

10.2.2 Other Cycloadditions The problems of controlling the regio- and stereochemical outcome in cycloaddition reactions are obviously not only restricted to the Diels-Alder reaction; the strategy of utilizing a temporary connection between reacting n systems to dictate the outcome of the reaction has also been applied to a variety of cycloadditions, including [2 + 21, [3 + 21, and [5 + 21 reactions. Since most of the tethering strategies resemble those used in the Diels-Alder reaction, only a few examples will be discussed here - a more comprehensive list of work can be found in the references.

10.2.2.1 Use of temporary tethering strategies in [2 + 21 photocycloaddition The [2+2] photocycloaddition between two olefin systems is the most efficient method for the preparation of cyclobutane rings [32-341. In the first asymmetric synthesis of stoechospermol 91, Koga and co-workers employed a tethering strategy to control the absolute stereochemical outcome of a key [2+ 21 photocycloaddition, which installed the correct stereochemistry at the two ring junctions [35]. By linking the two reacting olefins through an ester tether [32], it was anticipated that the cyclopentene derivative would be forced to react on the more hindered face of the enantiomerically pure butenolide, which is derived from (3-glutamic acid. This would provide a' route to the stereoisomeric cycloadducts obtained through the analogous intermolecular process in which cyclopentene derivatives had been previously shown to attack the butenolide anti to the hydroxymethyl substituent [36]. Formation of the ester cyclization precursor 92 was readily achieved as a 1 :1 mixture of diastereoisomers and, upon irradiation, afforded a 1 :1 mixture of cyclobutanes 93 differing only in the stereochemistry of the silyloxy substituent. The tether had therefore controlled both the regio- and stereoselectivity of the cycloaddition event. Subsequent manipulations afforded the desired natural product (Scheme 10-30).

0 OTBS

92

93

stoechosperrnol

91

Scheme 10-30 An ester tether was used to control the outcome of a [2+2] cycloaddition in Koga's synthesis of stoechospermol.

A similar tethering strategy was more recently used by Inouye et al. in their formal, racemic synthesis of precapnelladiene 94 [37]. The reacting enone and cyclopentene were linked through an ether tether. Irradiation of 95 in hexane effected cyclization,

300

10 Use of the Temporary Connection in Organic Synthesis

generating a single product 96 in which the tether had governed the relative stereochemistry at the ring junction and the initial stereocenter in the cyclopentene. Retro aldol fission of the 6-4 ring system provided an elegant entry into the desired bicyclo[6.3.0]undecane ring skeleton. Treatment with TMSI in benzene generated TMS enol ether 97, which was converted directly into diketone 98 by radical deiodination. Further manipulation into ketone 99 provided an interesting formal synthesis of precapnelladiene (Scheme 10-31).

TMSI,

P

PhH

95

(based on recovered starting material)

97

96

Bu3SnH, 98% from 96

precapnelladiene 94

99

98

Scheme 10-31 Inouye et al. used a [2 + 21 cycloaddition/retro aldol cleavage strategy in their formal synthesis of precapnelladiene.

10.2.2.2 An efficient synthesis of (-)-detoxinine using a tandem [4 + 2143 + 21 reaction Recent reports from the Denmark group have demonstrated the high synthetic utility of tandem [4+ 2]/[3 + 21 nitroalkene cycloaddition reactions in the preparation of pyrrolizidine alkaloids [38]. This methodology was recently applied to the synthesis of the unusual amino acid detoxinine 100 [39], which provides the central core in the detoxins, a family of depsipeptides displaying detoxifying activity against the nucleoside antibiotic blasticidin S. It was envisaged that a two-atom silyl tether between the heterodiene (nitroalkene) and dipolarophile would be ideal for controlling the outcome of the intramolecular [3 + 21 cycloaddition in the tandem step. Furthermore, the silyl tether would not only serve as a protecting group for the secondary alcohol on the pyrrolidine but would also provide a masked alcohol functionality for the pendant side chain. Oxidative cleavage of the tether would release this diol functionality at a late stage in the synthesis (Scheme 10-32).

- +?-Meo2c'1w 0 . ~ . 0 ,.OR'

0

OH

OH

-

'p,-sI-o

ipr Si-0

'P r!

detoxinine 100

1

masked dioi

iP:,os

'05

/j

intranpcular

t

R' = chiral auxiliary (provides absolute stereocontrol)

Scheme 10-32 Asilyl tether can control the stereochemical outcome of the tandem [4+2]/13+2]

reaction for application to the synthesis of detoxinine.

Formation of the silyl tether 101 was achieved in a highly efficient manner (Scheme 10-33).A silyllithium reagent, prepared from 'Pr,PhSiCl, lithium, and CuCN, was reacted with methyl (0-Piodoacrylate, affording the coupled product in excellent yield and with complete retention of configuration. Subsequent dearylation was best achieved with dry HCI in CHCI, at 80 "C,providing the silyl chloride 102 in almost quantitative yield. Reaction with the potassium enolate of nitroacetaldehyde then afforded the tethered cycloaddition precursor 101. In spite of bulky isopropyl substituents, 101 underwent hydrolysis during all purification attempts and was consequently used directly in the key tandem process. 0

Scheme 10-33 Preparation of the silyl tether was achieved in excellent yield.

Optimum conditions in the crucial tandem cycloaddition reaction involved the addition of the bulky aluminum Lewis acid, MAPh, to a cooled (-78 "C) solution of the silyl species 101 and the enantiomerically pure vinyl ether 103 followed by slow warming to -15 "C over 14.5 h (Scheme 10-34). Nitroso acetal 104 was then obtained in good yield as an inseparable 27: 1 mixture of diastereoisomers. The major product derives from

302

10 Use of the Temporary Connection in Organic Synthesis

initial ex0 addition of the s-trans conformer of the vinyl ether onto the si face of the nitroalkene. The subsequent [3 + 21 cycloaddition is controlled completely by the silyl tether with addition of the nitronate to the same face to which the tether is attached [40]. An endo-disposed tether also forces an ex0 orientation of the ester functionality of the dipolarophile (Scheme 10-34). Hydrogenolysis of the nitrosoacetal provided hydroxylactam 105 in 51% yield. With the silyl tether protecting the requisite diol functionality, selective removal of the superfluous alcohol functionality was facile using a radical deoxygenation protocol. Finally oxidative cleavage of the silyl tether - which proved surprisingly easy in spite of the bulky isopropyl groups - and hydrolysis of the lactam provided (-)-detoxinine in ten steps and 13% overall yield from commercially available 'Pr2SiC1, (Scheme 10-34).

[

P h 2

MeAl

0-

MAPh, -78 oc to -15v c , 14.5 h, 60%

i) radical deoxygenation ii) KF, H202, 105

(tether cleavage)

72% (2 steps)

HCI, reflux 90% deloxinine 100

Scheme 10-34 The tandem [4+2]/[3 +2] cycloaddition proceeded with excellent stereocontrol and allowed facile elaboration to (-)-detoxinine.

10.2 Cvcloaddition Reactions

303

10.2.2.3 Sulfur tethers in [5 + 21 cycloaddition The [5 + 21 cycloaddition reaction provides an interesting and potentially versatile entry into densely functionalized, seven-membered rings. However, it remains relatively unexplored. The reaction between 5-hydroxy-4-pyrones and alkenes has been shown to proceed only efficiently in the intramolecular cycloaddition mode [41]; cycloaddition in the analogous intermolecular variant either fails completely, or provides a mixture of stereoisomers. Mascareiias, Mouriiio, and co-workers chose to investigate temporary tethering strategies to overcome the problems associated with this bimolecular reaction [42J . Commercially available kojic acid 106 provides a convenient [5n]precursor since it contains a primary alcohol functionality as a suitable site for attaching the [2n]reacting partner. A number of tethers were investigated, among them a sulfide linker. The starting thioether 107 was readily prepared by standard procedures [42a]. Thermolysis of 107 in toluene at 145 "C for 40 h provided a single exo cycloadduct 108 in good yield. Treatment of the cycloadduct with Raney nickel effected desulfurization and rearrangement to ketone 109 in 70% yield (Scheme 10-35).The net result is equivalent to a formal intermolecular cycloaddition between an unactivated alkene and a-deoxykojic acid, a transformation which cannot be achieved by the bimolecular process. HO

TBSO

Oq--*-

OQ\

A PhMe

TBSO

RaNi,

145 "C, 71%

OH kojic acid 106

-

107

70% 108

109

Scheme 10-35 A sulfide tether allows [5+2] cycloaddition between an unactivated alkene and a pyrone.

The success of the sulfide tether encouraged the investigation of related tethers [431. A sulfoxide tether was readily accessed by mCPBA oxidation of sulfide 107. Since the sulfoxide provides a stereogenic center in the tether, it was envisaged that this might induce a degree of diastereofacial selectivity in the cyclization. Indeed, thermolysis of 110 in 1,2-dichloroethane provided a separable 3: 1 mixture of diastereoisomers in excellent yield (Scheme 10-36). Although the degree of asymmetric induction is modest, it once more illustrates the potential of using asymmetry in the disposable tether for imparting stereocontrol in the cyclization. It is also noteworthy that reaction with the sulfoxide tether proceeded at a more rapid rate at reduced temperature than with the corresponding sulfide. This result was attributed to a Thorpe-Ingold effect: increasing the substitution at the sulfur atom - by using a sulfone - would therefore be expected to facilitate the reaction further. This prediction was realized with cyclization of sulfone 111 proceeding readily at only 90 "C, again in excellent yield (Scheme 10-36).

10.2 Cycloaddition Reactions

305

The most simple method for connecting the two reacting fragments would be to combine the aldehyde and alcohol functionality into an ester. An aziridine acrylate precursor was readily prepared although all attempts to effect cyclization failed presumably owing to an unfavorable conformation adopted by the ester tether [45a]. A more flexible acetal functionality would possibly overcome these problems. Consequently, acetal 112 was synthesized as a 1 : 1 mixture of diastereoisomers in 77% yield by treating alcohol 113 with methoxyallene in the presence of mild acid. This time, photolysis of a dilute solution (0.001 M) of 112 in MeCN led to the isolation of a single stereoisomer 114 in 42% yield whose structure was confirmed by X-ray crystallography and was consistent with the desired endo-re mode of cyclization (Scheme 10-38) [45a, c]. Interestingly, only one of the acetal stereoisomers reacts; reaction of the other presumably requires a prohibitively high-energy T. s. to cyclize and instead is lost to non-productive side reactions. The outcome of this reaction was in accord with the group's T. S . model where the endo-re addition mode allowed the tether to adopt a conformation in which the controlling stereogenic center could place the smallest group (hydrogen) in the plane of the imide system, thereby minimizing A''3-strain and also allowing minimal distortion of the tether [45a, c]. + ,Me

n

0

,

1

Ph minimized

114 42%

Scheme 10-38 An acetal tether allows the desired endo-re cyclization to occur.

Examination of the X-ray crystal structure of the cycloadduct, not surprisingly, revealed appreciable strain in the molecule since the generated eight-membered ring contains a trans amide functionality. It was therefore anticipated that a longer, achiral tether would provide a better cyclization precursor. A rational design approach was taken to discover the optimal tether length [45b]. Initially, different tether lengths com-

I0 Use of the Temporary Connection in Organic Synthesis

306

prising sp3-carbon atoms were evaluated using computational modeling of the two competing (endo-si and endo-re) diastereoisomeric T. S.S. These results suggested that short tether lengths favored the desired endo-re cycloaddition mode, while the endo-si product would be formed preferentially at increased tether length. More refined T. S. modeling using the elements in the real tether supported these results. A number of different silicon tethers of varying length were prepared and the computational results were validated. Thus, with the formation of a nine-membered ring (from 115), the relsi ratio was 16:l (Scheme 10-39), while an increased tether length producing a 13-membered ring gave a reversal in selectivity with the endo-si product being the predominant species (relsi, 1 : 12) (Scheme 10-39). Tether cleavage was readily accomplished using standard protocols.

-

P h f q N M0 e

hv, MeCN

?

ph-si Ph/

Ph

115

16 (64%)

1

hv. MeCN

12 (46%)

Scheme 10-39 Varying the length of the silyl tether allows access to either endo-re or endu-si products.

Gamer and co-workers have once again illustrated the power of tether-mediated synthesis. In their example, the intermolecular reaction gave the undesired e m cycloadducts with no diastereofacial selectivity. Connecting the two reacting systems provided access to endo addition products. With further refinement of the tether length, the relsi diastereofacial selectivity was successfully addressed.

10.3 Temporary Tethering Strategies in Radical Cyclization Reactions

307

10.3 Temporary Tethering Strategies in Radical Cyclization Reactions 10.3.1 Introduction The bimolecular reaction between a radical and radical acceptor such as an unsymmetrically substituted, non-activated double bond, is an inefficient process and only in special circumstances is it regio- or stereoselective. However, when the radical and radical acceptor are connected through a tether, the ensuing intramolecular reaction is much more efficient, and frequently exhibits high levels of regio- and stereoselectivity, especially when small rings (e.g., five- and six-membered rings) are generated [46]. Such radical cyclizations have been investigated in detail and now find widespread application in organic synthesis as a versatile route to carbocycles. The high levels of control obtained in radical cyclization reactions may be exploited for acyclic regio- and stereocontrol by the use of a temporary connection, a strategy which was first investigated over a decade ago by Nishiyama and Stork, among others, and is now one of the most important applications of this method of intramolecularization. Of all the possible tethers which were discussed in the previous section on cycloadditions, silyl ethers, and to a lesser extent silyl acetals, have found most widespread use in radical cyclization reactions, primarily owing to their ease of formation and ready cleavage post-cyclization. Before examples of this form of templated synthesis are discussed, it is noteworthy that the presence of a silicon atom in the connecting tether can have a profound effect on the outcome of the cyclization. Baldwin has provided a series of rules which may be used to predict the relative ease of ring formation when a carbon-centered radical adds to a double or triple bond which is connected to the starting radical through a carbon chain [47].For example, with the 5-hexenyl radical, cyclization proceeds almost exclusively through the 5-ex0 mode providing a cyclopentane product (Scheme 10-40).Wilt and coworkers have shown that by replacing one of the methylene groups with a dimethylsilyl group, dramatic changes to both the 5-exo/6-endo ratio and the rate of reaction are observed [48].In particular, they found that with 2- and 3-silahex-5-enyl radicals, the 6endo cyclization mode was favored (Scheme 10-40).A number of factors are responsible for these changes in reactivity, including charge-stabilizin effects of the silyl group and the increased length of the C-Si bond (1.89 A; cf. 1.54 for C-C), which brings the radical center into closer proximity with the terminus of the double bond. The following discussion on the application of the temporary connection to radical cyclizations will be divided into five sections, In the first, a silyl ether is used as the tether in which one of the alkyl groups attached to the silicon possesses the radical precursor (usually a halogen). In the second section, it is the radical acceptor which is introduced on silyl ether formation. The third section concerns the use of silyl acetals as a temporary connection and in the fourth other templating strategies which do not fall into any of the aforementioned areas will be discussed. The final section is a discussion of the use of some of these strategies in C-glycosylation.

1

308

'

10 Use of the Temporary Connection in Organic Synthesis

0-0

5-ex0

favored

Scheme 10-40 2- and 3-silahex-5-enyl radicals preferentially undergo 6-endo cyclization (values in parentheses refer to the rate constants measured at 25 "C [ s-']).

pathway

favored pathway

favored pathway

10.3.2 Silyl Ethers Containing the Radical Precursor 10.3.2.1 The a-(bromomethyl)dimethylsilyl ether in radical cyclizations

(Bromomethy1)dimethylsilyl chloride is the most widely investigated and important reagent for incorporating a radical precursor into a silyl tether. It is commercially available and readily introduced as a silyl ether under standard conditions. Moreover, the facile cleavage of the silicon tether under a variety of conditions after reaction yet further enhances its synthetic utility.

Radical cyclizatwn onto a double bond Nishiyama et al. first introduced the (bromomethy1)dimethylsilyl ether group in a new method for the synthesis of 1,3-diols from allylic alcohols (491. Silyl ethers of a number of acyclic, allylic alcohols were readily prepared and, in a one-pot operation, heating a benzene solution with Bu3SnH/AIBN at reflux effected radical formation, and cyclization onto the double bond provided the cyclic products. These were exposed directly to a Tamao oxidation [ll], generating diols in good to excellent yields. The 5-eno-trig cyclization mode was found to predominate; only with terminally unsubstituted allylic systems were I ,4-diol products, derived from a 6-endo cyclization, observed (Scheme 10-41). The stereoselectivity of the process was also probed. For example, radical cyclization of (E)-allylic silyl ether 116 afforded an 84: 16 mixture of rhreoleryrhro diol products 117 and 118, respectively, while the corresponding (2)-isomer 119 generated the threo product 117 exclusively and in excellent yield (Scheme 10-41). These results are in accord with the Beckwith-Houk model for radical cyclization [50].

10.3 Temporary Tethering Strategies in Radical Cyclization Reactions

309

OH OH 100%

QH

OH OH

35 : 65

52%

9-

i), ii)

i ) , ii)

c-

(XSif- Br I\ 119

119

94%

117:118 1OO:O

116

85%

117: 118 8 4 : 16

Scheme 10-41 Synthesis of 1,3- and 1,6diols from (bromomethyl)dimethylsilyl ethers. Reagents and conditions: i) Bu3SnH; AIBN, PhH, reflux; ii) 30% H202, DMF, KF, 60 "C; iii) 30% H202,MeOH, THF, Na2C03,reflux.

Stork and co-workers extended this work with the application of the radical cyclization reaction to polycyclic systems, in particular steroids [5 11. Nishiyama had already shown that cyclization onto a cyclohexene generated exclusively the cis-fused bicycle 120 and the corresponding cis- 1,Zdisubstituted cyclohexane 121 on oxidative tether cleavage (Scheme 10-42) [49]. In this example, the quenching of the cyclized radical by H-abstraction would not affect the outcome of the reaction. However, with cholestenol derivatives 122 and'123, H-abstraction by the cyclized radical could provide either a trans- or a cis-fused A-B ring junction [51b]. This question was addressed by Stork: with the 3palcoho1, silyl ether formation and subsequent radical cyclization afforded, after reductive desilylation, the trans-fused product 124 in 75% yield, while the epimeric precursor 123 provided the cis-fused A-B ring junction 125 in similarly excellent yield and stereoselectivity (Scheme 10-42).In both cases, methylation occurred cis to the alcohol and H-abstraction occurred trans to the starting alcohol. This therefore amounts to a trans hydromethylation across the allylic olefin with the tether controlling the initial facial selectivity of the radical cyclization. The cupped nature of the generated polycycle provides sufficient steric differentiation between the two faces such that H-abstraction proceeds from the less sterically demanding convex face.

10 Use ofthe Temporary Connection in Organic Synthesis

3 10

radical cyclization

0-Si

Tarnao

o-si,

oxidation

OH OH

I

\'

121 75% (2 steps)

120

P

Br,,S -i

r

a

d

i

c

cyclization a l

/

0

@a@

9Si

I1&,-

DMSO

HO

'\

I

122

p

?*'

a

d

i

c

cyclization a l

'

S ,i

-Si-Br

I

0

123

\

-

124 75%

DMSo

HO"

& ~

125 80%

Scheme 10-42 Radical cyclization and reductive desilylation allows stereospecific methylation of steroids and formation of a cis or a trans ring junction.

Formation of a trans-fused 5,6-ring junction can sometimes also be achieved selectively. In an early example from Stork, radical cyclization of silyl ether 126 proceeded in 36% yield but with complete stereoselectivity affording the trans-fused hydrindane system [51a]. In this case, the methyl and O'Bu groups presumably reinforce the directing effect of the convex, newly formed silatricycle and H-abstraction is forced to occur from the sterically less hindered face (Scheme 10-43).

dQU trans

___)

addition only

?

-Si-Br 126

36%

Scheme 10-43 A trans-fused ring junction can be prepared selectively.

However, with other systems, the outcome of the final H-abstraction is less stereoselective. Jenkins and Wood have investigated the intramolecular radical cyclization onto cyclopentenols derived from glucose [52]. Two epimeric alcohols were prepared by reduction of enone 127 with either NaBH,/CeCl, (a/pratio 1:8) or L-selectride (alp

10.3 Temporary Tethering Strategies in Rudicul Cyclization Reactions

31 1

ratio 8 : 1). Subsequent reaction with (bromomethy1)dimethylsilyl chloride afforded the corresponding silyl ether radical precursors 128 and 129. Radical cyclization of the psilyl ether 128 provided the cis-fused 5,6-ring junction where H-abstraction had proceeded, as before, trans to the alcohol functionality. However, in the case of a-silyl ether 129, radical cyclization provided a mixture of products 130 and 131 in an unspecified ratio (Scheme 10-44). In this case, radical cyclization proceeds stereospecifically as normal, generating the cis-fused bicycle. If H-abstraction then occurs from the a-face (trans addition), a product possessing an energetically unfavorable trans-fused 5,6-ring junction is produced. As a result, the normally less favorable cis addition pathway leading to a cis-fused 5,6-ring junction can compete, leading to a more stable product.

Wo

Fhr

/O

127

~ , i i )

i ) l Y

128

iii)

trans addition

1

129

iii)

trans addition

cis addition

Scheme 10-44 H-abstraction is not always stereoselective. Reagents and conditions: i) NaBH,, CeCl,, 25 "C, 95%, then separate diastereoisomers; ii) (BrCH,)Me,SiCl, Et,N, CH,CI,, 89%; iii) Bu,SnH, AIBN, NaCNBH,, 'BuOH, 90 "C; iv) L-selectride, 91 %.

Controlled radical cyclization directly onto a ring junction is less easy. Lejeune and Lallemand envisaged that a tethered radical cyclization of a (bromomethyl)dimethylsilyl ether onto an allylic double bond could be used to incorporate a hydroxymethyl functionality into an angular position at the ring junction of a decalin system [53]. This would then provide an interesting entry into a variety of natural products containing this skeletal functionality, such as the insect antifeedant clerodin 132 (Scheme 10-45). Two diastereoisomeric allylic silyl ethers 133 and 134 were first investigated and in both cases, the desired radical cyclization products were not observed. In the case of 133, cyclization proceeded exclusively in a 6-endo mode, affording diol 135 after oxidative cleavage of the silyl linker. The preference for 6-ring formation was attributed to the conformational rigidity of the allylic system and the less hindered nature of the distal sp2-

10 Use oj'the Temporary Connection in Organic Synthesis

312

$2 H"

,\'

,\a.

0' clerodin 132

i iAc

. ,Si

1

-

,o

-

OH

\

angular hydroxymethyl group

Scheme 10-45 A silyl-tethered radical cyclization could be used to incorporate angular hydroxymethyl functionality at a ring junction.

carbon atom. Reaction was even less successful with silyl ether 134 and only the TMSether reduction product 136 was isolated, albeit in excellent yield. Thus, even with the advantages of intramolecularization, the desired radical addition cannot be guaranteed if the geometry is too rigid. The desired 5-ex0 cyclization mode could only be achieved by modifying the radical acceptor in 133. Enone 137 underwent stereospecific cyclization onto the more hindered ring junction in quantitative yield, affording the thermodynamically less stable cis decalin product 138 after tether cleavage (Scheme 10-46). In the case of 133 and 137, the axially oriented silyl ether allows the adoption of a pseudo-chair T. S. with axial attack on the olefin. This is not possible in the case of equatorially disposed silyl ether 134, rendering cyclization much less efficient. Temporary tethering of radical precursors has found other applications in natural product synthesis. Crimmins and O'Mahony utilized a silyl ether temporary connection to direct a hydro-hydroxymethylationof enol ether 139 in their synthesis of talaromycin A, 140 [54]. Since talaromycin A is susceptible to acid-catalyzed isomerization to the thermodynamically more stable talaromycin B in which the hydroxymethyl substituent is equatorial, the use of the essentially neutral conditions of a radical cyclization to install the requisite axial hydroxymethyl group would avoid any potential isomerization problems. Formation of enol ether 139 was achieved in five steps from (4R)-4-ethylvalerolactone 141. Exposure of 139 to Bu,SnH in benzene at reflux in the presence of AIBN as initiator effected radical cyclization with delivery of the radical to the same face to which the ether tether was attached. Tamao oxidation proceeded uneventfully, furnishing the desired natural product (Scheme 10-47). In most cases the radical generated after cyclization is quenched by H-abstraction. However, another possibility is to utilize the cyclized radical in another C-C bond-forming event. Fraser-Reid and co-workers utilized a silyl-tethered radical cyclization of the (L)-rhamnal-derived silyl ether 142 to generate the anomerically stabilized radical 143, which could be trapped in the presence of an excess of acrylonitrile to generate acetate 144 after tether cleavage and peracetylation (Scheme 10-48) [%a]. This reaction sequence occurred with complete regio- and stereoselectivity. The same group has also used an acetal tether (vide infra) to effect similar transformations [55b, 561.

10.3 Temporarq. Tethering Strategies in Radical Cyclization Reactions

cyclization Br 0si / \

6-endo

oxidation Si\

/

-0 radical

134

HO 135

45% (2 steps)

133

/ \

3 13

reduction product only quant.

/ \ 136

138 65% (from 137)

137

Scheme 10-46 Modification of the radical acceptor and appropriate choice of configuration of directing alcohol are necessary to ensure 5-exo cyclization.

I

30%

H202,

MeOH, Na2C03, 76% from allylic alcohol

Scheme 10-47 Crimmins and O'Mahony used a silicon-tethered radical cyclization in a synthesis of talaromycin A.

10 Use of the Temporary Connection in Organic Synthesis

314

AcO (OAc 142

144

143

Scheme 10-48 Fraser-Reid showed that the cyclized radical could be trapped with acrylonitrile. Reagents and conditions: i) 0.1 eq. Bu,SnCl, 2eq. NaCNBH3,AIBN, CH2=CHCN, ‘BuOH, reflux, 18h; ii) H202, KHCO,, KF, THF, MeOH, reflux, 12h; iii) Ac20, py, rt, 8h, 51% from (L)-rhamnal.

The potential for sila-hexenyl radicals to undergo 6-endo cyclization has already been alluded to. Mayon and Chapleur have shown that conformationally restricted exo- and endocyclic allylic (bromomethy1)silylethers derived from carbohydrate precursors react exclusively through the 6-endo mode of cyclization [57]. Koreeda and co-workers have also exploited this mode of cyclization to provide stereocontrolled routes to 22-hydroxylated steroid side chains [ 5 8 ] . 16a-(Bromomethy1)silyl ether 145 underwent radical cyclization and subsequent conversion to diol 146 in 66% overall yield. Similarly, the epimeric 16gradical precursor 147 reacted in good overall yield to give diol 148 (Scheme 10-49). Again, reaction through the 6-end0 cyclization mode may be rationalized on the basis of reduced substitution at C(20) compared with C( 17), and the conformational rigidity of the allylic system predisposing radical attack at the distal position of the olefin. It is also noteworthy that clean transcription of chirality is observed in the generation of two new stereocenters - net cis addition in the 16a-product and net trans addition in the 16P-isomer. Of further interest, the (bromomethy1)silyl ethers of the isoBr

Br

147

radical cyclization

oxidative tether cleavage

148

Scheme 10-49 6-Endo cyclization allows the stereocontrolled synthesis of 22-hydroxylated steroids.

10.3 Temporary Tethering Strategies in Radical Cyclization Reactions

315

meric (3-allylic alcohols afforded predominantly reduction products, suggesting the orientation of the methyl group at C(20) in these cases obstructs attack of the radical onto the olefin. Factors affecting the mode of cyclization have been investigated in more detail by the same group [59]. Wicha and co-workers have also demonstrated the utility of silyl-tethered radical cyclizations in functionalizing steroidal side chains [60]. Koreeda and Hamann have reported the use of silyl tethers in stereocontrolled syntheses of branched-chain 1,4-diols and 1,5-diols [61]. Exposure of (bromomethy1)silyl ethers prepared from the corresponding homoallylic alcohols with Bu,SnH in the presence of AIBN allowed smooth conversion to the corresponding cyclic siloxanes, from which diol products were obtained using standard, oxidative cleavage protocols. While monosubstituted olefin 149 selectively underwent 7-endo cyclization, di- and trisubstituted olefins 150 and 151 preferentially reacted through the 6-ex0 mode with complete stereocontrol, affording the diol products 152 and 153, respectively (Scheme 10-50).

\' i), ii)

151

153

Scheme 10-50 Silyl-tethered radical cyclizations may be used to prepare branched-chain 1,4- and 1,5-diols. Reagents and conditions: i) Bu,SnCl, NaCNBH,, AIBN, 'BuOH, reflux; ii) 30% H,O,, KHCO,, THF, MeOH, reflux.

The regio- and stereoselectivity may be rationalized in terms of the relative stability of the three possible T. S . conformations, which permit a 107-109" approach trajectory of the radical onto the sp2 center. Of the two T. S.s leading to 6-ex0 cyclization products, the one with a pseudoequatorially disposed olefinic group, is favored, leading to the observed 1,3-cis-disubstituted siloxanes. The regioselectivity of the cyclization is also noteworthy. The authors suggest that the preference of terminally unsubstituted olefins to undergo 7-end0 cyclization reflects the increased stability of the secondary radical intermediate over the primary radical which would result from an ex0 cyclization.

Radical cyclization onto a triple bond In a competition study, Malacria and co-workers have shown that a 5-exo-dig cyclization is appreciably faster than the 5-exo-trig process [62].The same group has exploited this

10 Use of the Temporap Connection in Organic Synthesis

316

efficient cyclization using the (bromomethy1)silylether group as a radical precursor. In some early work, they demonstrated a simple use of this reaction in an efficient synthesis of 2-[(trimethylsilyl)methyl]prop-2-en-1-01 (154) [63], which has found use as a precursor of trimethylenemethane in the palladium-catalyzed [3 + 23 cycloadditions investigated principally by Trost [64]. Formation of silyl ether 155 from propargyl alcohol proceeded uneventfully. Subsequent radical cyclization provided exclusively the 5-exo-dig product 156, which was not isolated owing to its instability; instead, treatment with MeLi generated the desired product 154 in 70% overall yield (Scheme 10-51).

155

156

154

Scheme 10-51 Formation of 2-[(trimethylsilyl)methyl]prop-2-en-I-ol(154).

When the triple bond is terminally substituted, 5-exo-dig cyclization and subsequent H-abstraction generate a trisubstituted double bond. Malacria and co-workers have shown that the configuration of the double bond can be controlled by varying the nature of the terminal substituent, thus providing a novel entry into stereodefined trisubstituted double bonds [65],which are not always easy to access via more conventional protocols. With alkyl substituents (e.g., 157), the reaction is highly stereoselective, giving rise to the (E)-olefin product 158 (Scheme 10-52). H-abstraction proceeds syn to the sterically more demanding substitution site. Since inversion of the cyclized radical proceeds more rapidly than H-abstraction, quenching will occur on the vinyl intermediate in which A'73interactions are minimized. Interactions between the H-donor and allylic substituents are not important in this case, owing to the angular nature of the radical. When the triple bond is substituted with a trimethylsilyl or a phenyl group (e.g., 159), stereoselectivity is reversed and now kinetically controlled, with H-abstraction providing predominantly the (a-olefinic product 160 (Scheme 10-52). This difference in reactivity may be attributed to a linear vinyl radical intermediate which is conjugatively stabilized by the terminal substituent removing A',3-interactions. Now, unfavorable steric interactions between the H-donor and the allylic substituents are product-determining. Radical cyclization reactions have found widespread use in the preparation of polyquinanes. A highly functionalized diquinane framework was prepared by Malacria and coworkers using a radical cascade process [66]. It was anticipated that the (bromomethy1)silyl ether 161 would serve as a suitable radical trigger. Thus, a solution of Ph,SnH and AIBN was added over 5 h to a benzene solution of 161 and 10 equiv of acrylonitrile at reflux. Further heating for 5 h followed by Tamao oxidation of the crude product mixture allowed isolation of diquinane 162 in 51% yield as a single stereoisomer (by 'H-NMR) (Scheme 10-53). More recently, the same group reported a route to linear triquinanes starting from acyclic precursors [67]. Once more, a (bromomethy1)silyl ether was used as the radical

10.3 Temporury Tethering Strategies in Radical Cyclization Reactions

317

angular radical

>si

/A

Bu

c zL i:;n+

0

Bu

Bu 157

i) H-donor ii) Tamao oxidation

HO

158

n

Ph3Sn-H Ph

HO

Bu

Bu

Bu

1OO:O

65%

linear radical removes A’*3-strain: interaction with H-donor now significant

radical cyclization

159

i) H-donor ii) Tamao oxidation

HO 25 : 75

160

84%

Scheme 10-52 Terminal substitution of the alkyne acceptor affects the stereochemical outcomc of the product olefin.

trigger. Previous attempts at effecting such a cascade process had been thwarted by the propensity for an intermediate radical to undergo intramolecular H-abstraction. However, in a carefully developed sequence, cyclization of 163 afforded the triquinane 164 in 50% yield (Scheme 10-54).

10.3.2.2 Other (haloa1kyl)dimethylsilylethers a-(Bromomethy1)silyl ethers are useful precursors for incorporating a one-carbon branch via a tethered radical cyclization. Koreeda and George have shown that this meth-

I0 Use of the Temporary Connection in Organic Synthesis

318

p+,, -

HO HO

Tamao oxidation

C5H11

Si

/ \

162 51% single stereoisomer

Scheme 10-53 Radical cyclization can be used to prepare diquinane 162 from an acyclic precursor.

-

Bu3Sn /I

P C N

5-exo-dig SOPh then 5-exetrig

7

Br

intermolecular reaction then 5-ewetrig

163

5-exedig

F c t - C N : P C N 9O:lO

& !-CN

I

‘SiMe3

‘11

9

1,5-H-abstraction @ !\ 0 CN

p-elimination

. 7 SOZPh pSiMe3 164 50%

PhSO; continues radical chain

)(’I.

n

) SOzPh

SiMe3

Scheme 10-54 Careful planning has allowed the preparation of triquinane 164 from an acyclic precursor.

od may be extended to incorporating longer alkyl chains with the preparation of (22R)22-hydroxycholestero1165from the allylic alcohol 166 (Scheme 10-55) [68]. The requisite (a-bromoalky1)silyl chloride 167 was prepared from 4-methylpentyne. Silylcupration with (PhMe,Si),CuLi .LiCN afforded the (E)-vinylsilane 168 after aqueous workup. Regioselective hydroboration, oxidation, and bromination then furnished the a-bromo-

10.3 Ternnoran, Tetherina Stratepies in Radical Cvclization Reactions

319

silane 169 in excellent overall yield. Although aryl silanes are stable to a wide variety of reagents, they are susceptible to halodesilylation and may therefore be considered masked silyl halides. Treatment of 169 with IC1 effected in situ generation of the desired silyl chloride 167, which allowed preparation of silyl ether 170 (Scheme 10-55).

Jvi)

-k

171

4:l

170

1

xii), xiii)

OH

Scheme 10-55 Koreeda's synthesisof (22R)-22-hydroxycholesterolby tethered radical cyclization. Reagents and conditions: i) (PhMe,Si),CuLi .LiCN, THF, 0 "C, 96%; ii) BH3 . THF, THF, 0 "C to rt, then H,O,, 3M NaOH, 60 "C, 82%; iii) Ph,PBr,, MeCN, 0 "C to rt, 81%; iv,v) ICl, CH,Cl,, reflux, then 166,Et,N, CHCI,, 0 "C to rt, 98%; vi) Bu,SnH, AIBN, slow addition, PhH, reflux, 65%;vii) purify by recrystallization; viii) KOH, DMSO, 60 "C, 65%; ix) 70% H202. KHC03, MeOH, THF, reflux, 75%; x) 2.6-dimethoxyphenyl chlorothionocarbonate, py, DMAP, CH,CI,, 0 "C, 88%; xi) TMSCl, py, 90%; xii) Bu,SnH, AIBN, PhMe, reflux, 91%; xiii) pPTS, EtOH, THF, 60 "C, 90%.

320

10 Use of the Temporaty Connection in Organic Synthesis

Radical cyclization of (a-bromoa1kyl)silyl ether 170 afforded a 4 : 1 mixture of 6-end0 cyclization products in addition to a small quantity of directly reduced product. The major diastereoisomer 171 was readily purified by recrystallization. Oxidative cleavage of the tether proved to be much more difficult than was initially anticipated, probably owing to steric blocking by the isoamyl group. It was found that the electrophilicity of the siloxane could be increased by treatment of 171 with KOH/DMSO, affording 172 as a 1 : 1 mixture of stereoisomers in 65% yield; this then underwent smooth oxidative cleavage. Selective deoxygenation at C( 16) exploited the slightly increased reactivity of this alcohol towards acylating reagents. Radical deoxygenation of the 22-TMS-ether derivative 173 proceeded smoothly in 9 1 % yield providing (22R)-22-hydroxycholesterol 165 (Scheme 10-55). Tamao et al. have investigated (dichloromethyl)dimethylsilyl ethers as radical cyclization precursors [69]. Silyl ether 174 was readily prepared from the commercially available silyl chloride and isophorol. 5-Em-trig cyclization could be effected under highdilution conditions, affording the bicycle 175 as a 6:4 mixture of stereoisomers. Subsequent oxidative tether cleavage afforded 2-formyl alcohols 176 and 177 where unfortunately, the presence of base caused partial epimerization of the center a to the formyl group (Scheme 10-56).

Scheme 10-56 A (dichloromethyl)dimethylsilylether can be used as a formyl radical equivalent. Reagents and conditions: i) (CI,CH)Me,SiCI, Et,N, Et20; ii) Bu,SnH (1.2 eq.),AIBN, PhH, slow addition, 80 "C; iii) 30% H20,, KF, KHCO,, THF, MeOH, rt, 5 1% from isophorol.

The retention of a halo-substituent after radical cyclization means that this tether may also be used as a hydroxymethylidene equivalent. A cis hydrindane ring structure could be formed from silyl ether 178 by treatment with 2.4 equiv of Bu3SnH under high-dilution conditions. Two successive 5-em-trig cyclizations provided tricycle 179 and a 4 : 1 mixture of stereoisomeric diols after oxidative cleavage of the silyl tether (Scheme 1057). The cis ring junction may be accounted for by the first H-abstraction proceeding from the convex face of the initially formed bicycle, and the major stereoisomer is a result of the second 5-ex0 cyclization occurring with attack on the terminal olefin from the concave face with an em-oriented olefin (Scheme 10-57). A trans hydrindane system was also accessible by trapping the radical intermediate resulting from the first cyclization with an ally1 group with net trans addition across the double bond establishing the desired trans ring junction (Scheme 10-57).

10.3 TemDorurv Tetherinr! Stradepies in Radical CvclizationReactions \ /

I

radical cyclization (2.4eq. Bu3SnH)

0-Si' ~

oxidation

\

170

fl

32 1

179

4: 1 cis hydrindane

'H-SnBu3 U

\ /

I

c1

2 eq. &SnPh, hv

i) 1.5 eq. Bu3SnH

@ I. t ''I-

ii) oxidative cleavage

H trans hydrindane

Scheme 10-57 Two radical cyclizations are possible with a (dichloromethy1)siIyI ether tether.

Radical cyclization of (pchloroethy1)silyl enol ethers has been investigated by Walkup et al. [70]. Cyclization in all cases proceeded through the 6-end0 addition mode, affording y-silyl alcohols in moderate yield after workup with MeLi. Net trans addition across the olefin double bond provides the major diastereoisomer.

10.3.2.3 Dimethylsilyl ethers possessing alkenyl and aryl radical precursors Tamao, Ito, and co-workers have investigated the use of silyl ether tethers in the radical cyclization of vinyl radicals [7 11. (1 -Bromovinyl)dimethylsilyl chloride was used to prepare the corresponding silyl ether 180 of isophorol. Radical cyclization using Bu$nH/AIBN in benzene (0.4 M) provided the two possible cyclization products 181 and 182, with the 5-ex0 product 181 predominating, along with the direct reduction product 183 (181/182/183 25 : 2 : 73). Formation of the reduction product could be suppressed using high-dilution conditions (0.02 M) (181/182/183 80 : 8 : 12). When tributylborane was used in place of AIBN as a radical initiator, a slight improvement in the 5-exoI6-endoratio was apparent (181/182/18376 :5 :19). The 5-ex0 product was formed stereoselectively in accord with previous examples with a net trans addition across the double bond. Tether cleavage was effected in a variety of manners, allowing elaboration of the major 5-ex0 product into the corresponding hydroxy ketone, homoallylic alcohol, and hydroxy vinyl bromide or silane (Scheme 10-58).

1

fiL[a+@-+d 10 Use of the Temporary Connection in Organic Synthesis

322

180

\ I

,Sid

o-~ I i'

S '.+i

/y

181

182

&&

183

or I")\ v)

g

f

3

Scheme 10-58 Radical cyclization of ( 1-bromovinyl)dimethylsilyl ethers proceeds primarily through a stereoselective 5-exo pathway. Reagents and conditions: i) Bu,SnH, Bu3B, PhH, 25 "C, products not isolated; ii) H202, KF, KHC03, MeOH, THF, rt, 62 % from 180; iii) 'BuOK, DMSO, H,O, rt, 62%from 180; iv) NBS, DMF, 0 "C to rt; v) Br,, CCI,, 0 "C then KHF,, MeOH, rt, 30% from 180; vi) MeLi, Et,O, 52% from 180.

When the (3-enriched 2-substituted vinylsilyl ether 184 was investigated in the same radical cyclization, only one cyclization product 185 was obtained with a (?)-configured vinyl silane [7 I]. This may be accounted for by a rapid equilibration of the vinyl radical prior to cyclization. While reaction of the (2)-isomer is favorable, in the corresponding (a-isomer, interactions between the terminal hexyl substituent and the cyclohexane ring render cyclization much less efficient (Scheme 10-59).

cyclization 184 €:Z10:90

1 C6H13

50% (from 184)

\

Tamao oxidation 185 (z)-isomer only

Scheme 10-59 Substituted vinylsilyl ether 184 reacts stereoselectively in a radical cyclization.

In an example from the Curran group, a silyl tether provides a method of incorporating a radical precursor into a molecule at a site remote from where it is desired [72]. 1 5

10.3 Temporary Tethering Strategies in Radical Cyclization Reactions

323

H-abstraction is generally a facile process, which often competes with desired transformations. However, in this case it can be utilized favorably to translocate the radical to the desired position for further reaction. The radical precursor in 186 is just a modified phenyldimethylsilyl ether and is much more readily incorporated than the alternative product, which would possess the radical precursor at the site of cyclization. Exposure of (o-bromopheny1)dimethylsilylether 186 to Corey’s catalytic tin hydride conditions [73] formed cyclopentane 187 as a 1 : 1.1 mixture of cislfrans isomers, in addition to some directly reduced product 188 (Scheme 10-60).

186

1

1

direct reduction

OSiMepPh

OSiMezPh COPEt

188

22:70

187 61% (isolatedyield)

Scheme 10-60 A silyl tether provides a more readily prepared radical precursor for effecting cyclization.

10.3.3 Silyl Ethers Containing the Radical Acceptor Previous examples of silyl-tethered radical cyclizations have involved the incorporation of the radical precursor during the formation of the silyl ether tether. An alternative would be to incorporate the radical acceptor. A number of suitable silyl chlorides are commercially available which facilitate the preparation of such cyclization precursors. In an early example, Hiemstra, Speckamp, and co-workers demonstrated the synthetic utility of this form of tether-directed radical cyclization in a formal synthesis of the p hydroxy-y-amino acid, statine 189 [74]. Diacetate 190 was readily prepared in three steps from (S)-malic acid. Under normal circumstances, treatment of 190 with a Lewis acid effects formation of the corresponding N-acyliminium intermediate which may be trapped intermolecularly with a nucleophile, preferentially from the less hindered face, affording a truns-substituted lactam (Scheme 10-61). For the purposes of a synthesis of statine however, a cis-substitution pattern was desired. It was envisaged that this might be achieved using a tether-directed radical cyclization. To that end, incorporation of a thiophenyl radical precursor was achieved by transacetalization. Subsequent deacetylation and silyl ether formation using aminosilane 191 generated the radical cyclization precursor 192. Radical cyclization proceeded exclusively in the 5-exo mode affording

10 Use of the Temporary Connection in Organic Synthesis

324

the cis-fused bicycle as an inconsequential 3 :2 mixture of stereoisomers. Subsequent reductive cleavage of the silyl ether allowed conversion into lactam 193 which had been previously converted to statine 189 by Johnson and co-workers (Scheme 10-61) [75]. AcO

A d

threestepsHO&

.A?&~

C02H

(S)-malic acid

190

BFpOElZ

Ph

95%

intermolecular alkylation provides the trans product

trans : cis

9:l

i) EtOH, EtONa (cat.) AcO

ii) Me2C=CHSi(Me)2NMe2) 191

190

Ph

38% (2 steps)

'

75%

192 Ph

I __ & 3:2

I) TBAF, CsF, THF

ii) Na, NH3(1)

72% (2steps)

0

&OH

on o statine 189

BOC

n

0

193

Scheme 10-61 A tether-directed radical cyclization provided the key step in the formal synthesis of statine 189 by Hiernstra, Speckamp, and co-workers.

C-branched nucleosides have been found to possess a number of biological properties, including antibacterial, antitumour, and antiviral activity. This has fueled a drive for preparing novel analogs of such molecules. Chattopadhyaya and co-workers have published extensively on the manipulation of nucleosides using intramolecular radical cyclizations [76J, which are camed out under mild and, importantly, neutral conditions, making them compatible with a range of functionality. In an early example, the incorporation of phenylseleno functionality into the 3'-position of a number of thymidine nucleosides allowed the stereoselective preparation of 3'C-branched derivatives (Scheme 10-62) [76a]. An ester tether was used to connect the radical acceptor olefin functionality to the 5'-hydroxy group. Radical cyclization of 194 under high-dilution conditions using Bu,SnWAIBN in benzene at reflux afforded the corresponding Glactone bicyclic products 195. In all cases, retention of configuration was observed at the site of radical generation with the formation of cis-fused bicycles. Furthermore, only products resulting from a 6-ex0 cyclization mode were isolated. Cyclization through a chair-like T. S. with a pseudo-equatorially disposed substituent accounts for the observed stereoisomer. Hydrolytic cleavage of the tether proceeded efficiently with aqueous ammonia, generating the corresponding hydroxy acids 196 in excellent yield (Scheme 10-62).

10.3 Temporary Tethering Strategies in Radical Cyclization Reactions

T = thymine

R = H 10% R:Me 50% R = Pr 53%

325

R = M e 95% R = Pr 94%

Scheme 10-62 Tethering the radical acceptor and precursor through an ester linkage allows

stereoselective radical cyclization of 3’-phenylseleno thymidine nucleosides.

The same group have also investigated the incorporation of the radical acceptor moiety via a silyl ether tether [76b]. A phenylseleno substituent was stereospecifically incorporated into either the 2’- or 3’-position of four thymidine nucleosides, followed by incorporation of an olefinic radical acceptor into the vicinal hydroxyl group by reaction with (allyl)dimethylsilyl chloride. In all cases, only products resulting from a 7-endo cyclization mode were isolated after treatment with Bu,SnB/AIBN. The stereochemical outcome of the reaction decended on the configuration of the (ally1)silyl ether group. In the cases of 197 and 198, regardless of whether the radical was generated at the 2‘- or 3’-position, cyclization onto the ally1 group on the a-face provided single diastereoisomeric cis-fused bicyclic products 199 and 200 in good yields. However, when the radical was trapped on the pface, reaction either afforded a I : 1 mixture of cis- and trans-fused bicycles in the case of 201; or the unusual tetracyclic product 202 resulting from further reaction with the proximal thymine base (Scheme 10-63). Oxidative cleavage of the silyl tether afforded the corresponding 1,5-diol products in good yields. Chattopadhyaya and co-workers have also demonstrated that alkynyl groups can be used as radical acceptors when linked through a silyl ether [76c]. Radical cyclization and subsequent oxidative cleavage of the tether provided access to 2’- and 3’-C-branched aketo-P-D-ribonucleosides,usually in good to excellent yields. In a more recent study on the use of silyl-tethered radical cyclizations for the preparation of 4’-a-C-branched-2’-deoxyadenosines, Shuto, Matsuda, and co-workers observed an interesting dependence of the apparent mode of cyclization on the reaction conditions [77]. The known 4’-phenylseleno derivative 203 of 2’-deoxyadenosine was readily converted to the 3’-vinylsilyl ether 204 using standard conditions. Treatment of 204 with 3 equiv of Bu,SnH at 80 “C in benzene, using AIBN as radical initiator followed by oxidative tether cleavage, provided a 2 :1 diastereoisomeric mixture of diols, 205 being derived from a 5-ex0 cyclization mode (Scheme 10-64). However when the Bu3SnH/AIBN was added slowly over 4 h to a solution of 204 at 1 10 “C, maintaining a low concentration of Bu,SnH, a reversal in regioselectivity was observed with the diol 206 being obtained after Tamao oxidation (Scheme 10-64).The results suggested that the

10 Use of the Temporary Connection in Organic Synthesis

326

MMTrovT radical

.si

,o

'U

Seph

cyclization, 63%

Tamao oxidation, 89%

-Si /

197

HO

199

Tamao oxidation, 81%

radical

__2_

cyclization, 69%

OH

200

198

'

cyclization

201

Tamao

hiso 0

'

cyclization, radical

SePh

62%

MMTrO'\

oxidation, TamaoD

70%

0

" M T t O w H o H

H

H O H

202

Scheme 10-63 The stereochemical outcome in the silyl-tethered radical cyclization of nucleosides is dictated by the configuration of the silyl ether group.

formation of the 6-end0 product 207 was under thermodynamic and not kinetic control, since the endolexo ratio would not be expected to change upon varying the concentration of Bu,SnH if the reaction was kinetically controlled. A mechanism was proposed which may account for these observations (Scheme 1065). In both cases, radical cyclization proceeds in the normal 5-exa-trig mode affording the intermediate radical 208. At low concentrations of Bu,SnH, rearrangement to the more stable secondary radical 209 is possible and this species is then quenched by Habstraction. The precise mechanism of the rearrangement is not known although it may proceed via a fragmentation-recombination process or through a silicon-bridging intermediate.

10.3 Temporary Tethering Strategies in Radical Cyclization Reactions

327

NHBz

P h W A b z DMTrO

* -' @SiPhpCl DMAP, EtsN,

HO

93%

203

91%

Ph. .o phSi

I 1 DMTwAbz \\

A = adenosine

BusSnH, (low conc.),

Ph' b h

204

Bu3SnH, (high conc.)

Tamao oxidation, 98% from 204

HO

207

Tamao oxidation, 79%

DMT

Ph-Si. Ph'

Ho

HO

205

206

Scheme 10-64 The concentration of Bu,SnH can be crucial in determining the product outcome. DMTrO

DMTrO

DMTrO

Ph

\

4

\

DMTrO

I """"Hb DMTwAb= Ph

at high conc. of BusSnH, radical trapped before it can rearrange

Ph-Si Ph' ' 0

208

ph c Si I '0 Ph

BusSnH

si *O

Ph'bh

207

Scheme 10-65 A possible mechanism to account for isolation of a 6-end0 addition product.

10.3.4 Silyl Acetals Silyl acetals have been investigated by Hutchinson and co-workers as tethers in radical cyclization reactions [78]. A number of commercially available dialkyldichlorosilanes were investigated as tether precursors although 'Pr2SiCI2 was found to be the most suit-

328

I0 Use ofthe Temporary Connection in Organic Synthesis

able, providing a compromise between hydrolytic stability and ease of introducing the second alcohol group. 2-Bromoethanol was used as the radical precursor throughout the study while the radical acceptor was varied. The unsymmetrical silyl acetal unit was best prepared in a stepwise procedure: treating 'Pr,SiCl2 with a three-fold excess of 2-bromoethanol allowed isolation of the monochlorosilane 210 by distillation in 60% yield. Subsequent reaction with a variety of radical acceptors (hydroxyalkenes and lithium enolates) generated the silyl acetals in good to excellent yield (Scheme 10-66).

210

Scheme 10-66 Stepwise preparation of silyl acetals.

Radical cyclization using standard Bu3SnH/AIBN conditions revealed a preference for the formation of the larger of the two possible rings via an endo-trig cyclization, although in some cases it was possible to induce the exo-trig cyclization by polarizing the radical acceptor (Scheme 10-67). The preferential 7-endo-trig cyclization is in contrast with the 6-ex0 trig cyclization observed with silyl ethers (vide supra). In some cases, a reduction product was also obtained. Deuteration studies using Bu,SnD indicated that this product arose from a competing intramolecular H-abstraction. Cleavage of the tether was possible using standard acidic hydrolysis or by treatment with TBAF (Scheme 10-67). The preparation of medium-sized rings can be problematic; however, in this case there are a number of factors which may account for the observed facility of ring formation and regioselectivity. These include the relatively long Si-0 bond, large 0-Si-0 bond angle (Si-0 bond 1.64 A; 0-Si-0 angle 149") and silicon anomeric effects. Furthermore, the presence of two oxygen atoms in the ring reduces unfavorable transannular interactions. A highly convergent approach was taken by Myers and co-workers in their elegant synthesis of tunicamycin V, 211 [79]. In a key step, a silyl acetal tether-directed radical cyclization was used to unite the uridine nucleoside with the disaccharide fragment, which contains an unusual "trehalose" glycosidic linkage. The silyl acetal radical precursor was prepared in a single operation from the allylic alcohol 212 and uridine 5'-aldehyde 213. Thus 3 equiv of pyridine were added dropwise to a toluene solution of the aldehyde (2 equiv) and PhSeH (3 equiv) and this mixture was then added to a solution of Me,SiCI2 (20 equiv) in pyridine. After 4.5 h at 23 "C,removal of the volatiles provided

10.3 Temporary Tethering Strategies in Radicul Cyclization Reactions

329

,C02Me

'Pr'

Si \

'

cyclization

OfiBr 0 -

HO

exclusively 9-endo

Br

'p 'Pr, ,.s:

MeOH, 22% (2 steps)

!Pr'

radical cyclization,

P l rs.("-) Pr'

-

exclusively 8-endo

8-endo

7 : 93

7-ex0

Scheme 10-67 Radical cyclization of silyl acetals proceeds preferentially via the endo-trig mode.

the crude monochloride. Addition of the allylic alcohol 212 in pyridine to a solution of the intermediate monochloride in toluene effected rapid conversion to the silyl acetal 214, which could be isolated in a very impressive 81% yield after purification by flash column chromatography (Scheme 10-68). The protecting groups on the 2'- and 3'-hydroxyl groups of the ribonucleoside were found to have a marked influence on the configurational outcome at the C(5') stereocenter in the radical cyclization. In all cases investigated, use of Bu,SnH with Et,B as a radical initiator allowed efficient conversion to the desired cyclic siloxane; however, the use of sterically bulky TBS ethers on C(2') and C(3') gave rise to the undesired stereochemistry at C(5'). This was attributed to destabilizing steric interactions between the glucosamine residue and the 3'-silyl ether in the T. S. leading to the desired product, which were not present in the T. S. leading to the epimeric product. Consequently, the radical cyclization was ultimately carried out on the free diol215 (Scheme 10-69). It was anticipated that the diminished size at C(2') and C(3') would not only reduce unfavorable steric interactions but the desired T. S. would even be preferred owing to the presence of a hydrogen bond between the C(3')-hydroxyl group and the glucosyl amide oxygen atom. Cyclization in toluene at 0 "C provided the desired product 216 with the correct configuration at C(5') (7.5 : 1 ratio). Use of the silyl acetal not only ensured highly efficient coupling of the two fragments but subsequent cleavage of the siloxane tether could also be achieved under very mild conditions using KF . 2 H,O in MeOH, affording the sensitive tetraol 217 in an excellent yield of 60% from 215 (Scheme 10-69). Subsequent manipulations allowed the preparation of tunicamycin V [79b].

10 Use of the Temporary Connection in Organic Synthesis

330 0

NBOC

0

I NAo

H RO OR

i) PhSeH, py ii) MenSiClP

RO

OR

212

1 PY

213 R = C(O)OCH&H=CHz

0

214 81% from 213

Scheme 10-68 Preparation of the key silyl acetal tether in one step, during the synthesis of tunicamycin V. 7.51

\ o

0 PhSe

HO

OH 215

I"". 1 KMH20,

I

I

M)% from 215

Scheme 10-69 Radical cyclization on the 2',3'-diol provided the desired configuration at C(5') and allowed elaboration to tunicamycin V.

10.3 Temporary Tethering Strategies in Radicul Cyclization Reactions

10.3.5

33 1

Acetal Tethers in Radical Cyclizations

Although the (bromomethy1)silylether connection has been more extensively utilized in radical cyclizations, Stork also introduced, at a similar time, the use of a mixed acetal function [51a, 73b, 801. This tether differs in that a two-carbon unit is introduced on the proximal carbon atom of the olefin, whereas the silyl tether allows the incorporation of only one carbon atom. The chemistry of this tether is dominated by 5-exo-trig cyclizations onto allylic double bonds which proceed with the usual degree of high stereoselectivity. Two examples in natural product synthesis will serve to illustrate the regio- and stereodirecting ability of this tether system. In the first example, Stork and co-workers used an acetal tether to direct a radical cyclization for incorporating the trans relationship between the pendant chains in prostaglandin FZa [8 11. Treatment of enantiomerically pure monosilyl ether 218 with ethyl vinyl ether in the presence of NIS provided the mixed iodoacetal radical precursor 219 in excellent yield. Introduction of the “lower” side chain was then approached in two ways. In the first, radical cyclization of 219 was effected using the Bu3SnC1/NaCNBH,/AIBN system and the cyclized radical was trapped with tert-butyl isocyanide, providing nitrile 220 in 7 1% yield as a single stereoisomer (Scheme 10-70). In accord with the radical cyclization of a-(bromomethy1)silyl ethers, 5-em-trig cyclization produced the bicyclic intermediate radical which was then trapped exclusively from the convex face with tert-butyl isocyanide. The presence of the a-silyl ether group enhances the trans selectivity by further blocking the concave face of the bicycle. Subsequent introduction of the rest of the side chain proceeded uneventfully with reduction of the nitrile to the corresponding aldehyde followed by Wadsworth-Emmons homologation using the Masamune-Roush conditions [82]. In a second approach, 2-(trimethylsilyl)oct-l-en-3-onewas used as the radical trap, enabling incor-

0 OH

TBSO.

218

radical cyclization

-

TMS

i) + c ~ H ~ ~ 0

L

TeSO

L

’Bu-NC

I

A

ii) thermal TBSO rearrangement

OTMS

221

OEt i) reduction

ii) Wadswoftk Emmons

220

93% (2 steps)

71% (from 219)

Scheme 10-70 Use of two radical traps to incorporate the “lower” side chain of prostaglandin F2a.

I0 Use of the Temporary Connection in Organic Synthesis

332

poration of the whole side chain in one step. The presence of the a-(trimethylsilyl) group was crucial for ensuring regioselective re-incorporation of the enone functionality. Radical cyclization proceeded efficiently as before with the expected excellent regio- and stereoselectivity to give, after thermal rearrangement, TMS-enol ether 221, which allowed regioselective incorporation of the olefin functionality with a Saegusa oxidation (Scheme 10-70) [83]. Enone 222 was obtained in 58% yield over the three steps. Completion of the synthesis was readily achieved. Diastereoselective reduction of the ketone was accomplished with (S)-BINOL/LiAlH,. Then, removal of the tether by acidic hydrolysis, which also effected silyl ether deprotection, afforded dihydroxy lactol223 allowing introduction of the final side chain using a Wittig reaction (Scheme 10-71).

(S)-BINOL, LiAIH4,THF,

-100 "C, 89%

TBSO' C5Hll

HCI I THF, 98% OH

c5~~Hz)3cozH "'

\=/

HO

HO. prostaglandin FPa

I

HO

+

BC

PhBP -(CH~)~COZK,

*

KO'Bu, THF, 62%

H0 ' HO

Scheme 10-71 Stork's synthesis of prostaglandin FZa.

Another example of the use of mixed acetal functionality to direct a radical cyclization is found in Rama Rao's synthesis of the C( 1)-C(9) fragment of the antitumor macrolide antibiotic rhizoxin 224 [84].In this case, Rama Rao utilized a 6-ex0 radical cyclization to generate the desired 1,3-syn relationship between the substituents on the &lactone 225. Starting from alcohol 226, treatment with ethyl vinyl ether in the presence of NBS produced the radical precursor. Stereoselective radical cyclization produced exclusively the 6-em-trig addition product 227. The stereochemical outcome of the reaction may be accounted for by cyclization proceeding through a chair-like T. S . with pseudoequatorially disposed substituents generating the desired syn relation. Subsequent manipulations including hydrolysis of the tether and oxidation of the resultant lactol provided the desired lactone product 225 (Scheme 10-72).

10.3 Temporary Tetherinn Stratecies in Radical Cvclization Reactions

SiO

pOEt'-

Bu3SnCI, NaCNBH3,

sio%

NBS,

OEt

226

0

88%

OEt

~

AIBN, %OH, 78%

05'

C02Et

J

L

0

1

333

Si = TBDPS

+7

.OEt

SiO

==3

s

EtO

i

o

q COPEt

227

0

225

Scheme 10-72 Synthesis of the C(1)-C(9) fragment of rhizoxin in which Rama Rao used an acetal tether to direct a radical cyclization.

10.3.6 Tether-directed Radical Cyclization Approaches to the Synthesis of C-Glycosides Stork first demonstrated the use of the temporary silicon connection in stereospecific Cglycoside synthesis [2]. (Pheny1ethynyl)silyl ethers were prepared from a number of phenylseleno glycosides. Generating the anomeric radical by treatment with Bu,SnH/ AIBN in benzene at reflux effected efficient radical cyclization onto the tethered alkynyl group in a highly stereocontrolled manner. Thus, a PC-glycoside could be obtained by tethering the radical acceptor to a &oriented hydroxyl group, while tethering to an a.~ oriented hydroxyl group allowed access to the corresponding a-C-glycoside (Scheme 10-73). In all three cases outlined in Scheme 10-73, cyclization proceeds in an e m mode. For the 2-substituted glucoside 228,5-exo-dig cyclization was extremely efficient, providing the desired u-C-glucoside 229 in an excellent 83% yield after silyl deprotection with TBAF. Attaching the radical acceptor to the 3-hydroxyl group allowed an efficient 6-exodig cyclization to proceed, generating alcohol 230 in 73% yield. The high yield of this process is particularly noteworthy since the sugar must undergo a conformational change in which the 3-silyloxy group adopts an axial orientation to ensure close proximity to the radical generated at the anomeric center. When the radical acceptor was attached to the 6-hydroxyl group, slow addition of the Bu3SnH was required to maintain a good yield of the less favorable 7-exo-dig cyclization product. Once again the reaction was completely stereospecific, generating the PC-glucoside 231. In all cases examined, an (a-styryl group was produced as the major product, often with excellent stereocontrol. ~

10 Use of the Temporary Connection in Organic Synthesis

334

0

SePh

EZ1O:l’

Ph

83% (from 228)

I

€:z>20:1 73% (2 steps)

Ph

,si

-+’“

’

\ /Ph I

ii)

7-ex0 BBnOn BnO t aSePh

BnO

BnO BnO

Ph BnO

231 54% (2 steps)

Scheme 10-73 Intramolecular radical cyclization provides a stereospecific route to a-and PCglycosides. Reagents and conditions: i) Bu3SnH,AIBN, PhH, reflux,0.01 M,(syringe pump used in 6-ex0 cyclization);ii) TBAF, THE

The introduction of an olefin at the anomeric position is synthetically interesting as it permits, via ozonolytic cleavage, access to the anomeric aldehyde, useful for further manipulations. Furthermore, the cleavage of the tether after cyclization releases one hydroxyl group selectively, which may be used chemoselectively in subsequent reactions. This reaction was also shown to be applicable to furanose sugar derivatives [2]. Sinay and co-workers have extended this type of reaction to the preparation of Cdisaccharides [W]. These molecules are conformationally similar to normal disaccharides but since the interglycosidic oxygen is replaced with a methylene group, hydrolysis of the glycosidic linkage is prevented. A 9-endo-trig radical cyclization of silyl a c e d 232,which had previously been shown to be viable by Hutchinson et al. [78], was used to prepare the methyl a-C-disaccharide 233 (Scheme 10-74) [85a]. A stepwise procedure was used to prepare the radical cyclization precursor: an excess of Me2SiC12was first added to the lithium salt of phenylseleno glycoside 234 at low temperature. After warming to room temperature and removing the volatiles (including the excess Me2SiC1,) in vacuo, a solution of the primary alcohol 235 and imidazole in THF was added, allowing formation of the second silyl ether linkage. This procedure allowed isolation of silyl acetal232 in an impressive 95% yield. Slow addition of Bu3SnH and AIBN to a solution of 232 maintained a low concentration of tin hydride and provided the cyclization product

10.3 Temporary Tethering Strategies in Radical Cyclization Reactions

335

233 as a single diastereoisomer in 40% yield after cleavage of the silyl tether (Scheme 10-74). (Spectroscopic analysis of 233 suggested that the C-glucosyl moiety deviates from the 4C1 chair form - hence its depiction in the Haworth representation in the scheme.)

:T=sep,, BnO

i) BuLi, THF ii) MepSiCIz,

OH

~

-70 "C to 22 "C

234

235

OMe

THF, irnidazole,

2h

%

BnO

i ) Bu3SnH, AIBN,

slow addition, PhH, reflux

+

ii) HF, THF

HoBnO

233 40%

BnoOMe 232 95%

Scheme 10-74 9-endo-trig radical cyclization used by Sinay in the synthesis of methyl a-C-maltoside 233.

The same group used a ketal tether as an alternative connecting group in the synthesis of the 1,4-linked C-disaccharide 236 [85b]. Tebbe methylenation of acetate 237 provided the corresponding enol ether 238, which upon treatment with alcohol 235 in the presence of CSA at -40°C in acetonitrile, furnished linked disaccharide 239 in 81% yield. Subsequent radical cyclization, acidic hydrolysis of the tether and peracetylation provided the D-mannose-containingC-disaccharide 236 as the major product in 35% yield from 239 (Scheme 10-75). Cyclization was not completely stereoselective and a small amount of the PC-manno isomer was also isolated (alp 10: 1). This result is in contrast to similar studies on tether-directed PO-mannoside syntheses (vide infra) where a much shorter tether attached to the axial 2-hydroxyl group forces obtention of the desired P configuration. The C-glycosylation strategy described above is, in principal, quite general and has been alikened to an enzymatic reaction in which the tether provides the pre-organizing role of an enzyme (a C-glycosyl transferase), the seleno glycoside is the glycosyl donor, and the exo-methylene sugar the glycosyl acceptor. The Bu3SnH plays the role of coenzyme and initiates the reaction. Although phenylseleno sugars have been most frequently used as radical precursors, their preparation requires the use of odorous phenylselenol. Furthermore, formation of the anomeric radical usually requires Bu3SnH, which is also unpleasant to work with. An

336

10 Use ofthe Temporary Connection in Organic Synthesis

87% 237

SePh

238

SePh

235

CSA, 4A rns,

CHzCN, -40 "C, 81%

i) BuSSnH, AIBN, PhH, reflux ii) TFA, H20, CH2ClP iii) A g o , py 236

35% (3 steps)

239

SePh

Scheme 10-75 A ketal tether was used in a 9-endo-trig radical cyclization to prepare C-disaccha-

ride 236.

alternative and more environmentally friendly approach to the same goal, of generating a radical at the anomeric position of a sugar, is to use single-electron transfer from samarium diiodide to anomeric sulfones. Anomeric phenyl sulfones have been investigated as radical precursors by Sinay and co-workers and shown to participate in efficient radical cyclizations similar to those described above [85c]. One disadvantage of using phenylsulfones however, is the need for the carcinogenic cosolvent HMPA to increase the reducing potential of the SmI,. Fortunately Skrydstrup, Beau, and co-workers have shown that the more readily reduced 2-pyridyl sulfones circumvent the need for adding HMPA - reaction proceeds in THF alone [86]. Using this methodology, they prepared methyl a-C-isomaltoside 240 in 48% yield from the tethered precursor 241 (Scheme 1076). In this example, a short tether length ensured exclusive formation of the a-C-glycoside.

i) Smlp, THF ii) TBAF, THF

?

iii) Pd I C, H2 iv) AczO, PY 241

BnO

Me0

48%

240

OMe

Scheme 10-76 A 5-exo-dig cyclization initiated by the action of SmI, on 2-pyridyl sulfone 241 allowed the preparation of a-C-isomaltoside 240.

10.4 Use of the Temporary Connection in 0-glycosylutionand Nucleosidution

337

10.4 Use of the Temporary Connection in 0-Glycosylation and Nucleosidation 10.4.1 Tether-Directed 0-Glycosylation The last decade has seen a resurgence in oligosaccharide chemistry. This has been fueled by an increasing realization of the important role oligosaccharides play in a wide variety of biological processes ranging from viral and bacterial adhesion to cells, protein trafficking, and intercellular recognition [87]. Access to complex oligosaccharides from natural sources is possible, although usually only in small quantities. One method of providing larger quantities of these important molecules is through chemical synthesis. Although the field of carbohydrate chemistry has been intensively studied, regio- and stereoselective glycosylation remains a difficult problem which usually relies on elaborate protecting group strategies for controlling regioselectivity (i.e., reaction at the appropriate hydroxyl group) and the use of an array of activation strategies for performing the actual glycosylation reaction, which all too frequently give a mixture of a-and p-anomers requiring tedious separation. Stereocontrolled glycosylation where either aor panomer linkage is obtained in a predictable manner remains an important area of research [88]. Synthesis of the Pmannopyranoside linkage is notoriously difficult since the axial hydroxyl group in the 2-position favors the formation of the a-anomer on both steric and electronic grounds. This problem is compounded by the fact that it is an important glycosy1 linkage found in the pentasaccharide core 242 of all asparagine-linked glycoproteins (Figure 10-6);efficient and stereoselective routes to the synthesis of this linkage are therefore highly desirable.

HO

Figure 10-6 The pentasaccharide core of all asparagine glycoproteins contains p-1,Clinkage

242

a pmannoside linkage.

The groups of Hindsgaul and Stork addressed this problem using a temporary connecting group to force intramolecular delivery of the glycosyl acceptor to the pface of the mannosyl donor. Barresi and Hindsgaul chose to use an acetal tether to connect the reacting partners [89a]. For example, formation of the mixed acetal 243 was achieved by reacting enol ether 244 with glucosyl acceptor 245 in the presence of catalytic pTSA. Subsequent glycosylation was initiated by NIS, affording exclusively the desired p-

338

10 Use of the Temporary Connection in Organic Synthesis

linked disaccharide 246 in 42% yield. It was later found that the addition of 4-methyl2,6-di-rerr-butylpyridine(4-Me-DTBP) improved the yield further, especially in the case of less reactive secondary alcohols, presumably by preventing decomposition of the acetal tether prior to the glycosylation step [89b]. With these modified conditions, disaccharide 246 could be obtained in a very respectable 77% yield, again as a single stereoisomer (Scheme 10-77).

5 eq. NIS,

5 eq. 4-Me-DTBP, -5 "C to rt, 16h,

77%

BnO 246

bhne

Scheme 10-77 Tethering the glucosyl acceptor through an acetal to the 2-OH of the mannosyl donor affords exclusively the /3- 1,Clinked mannoglucoside.

The proposed mechanism of reaction is outlined in Scheme 10-78. Activation of the anomeric group is followed by intramolecular delivery of the glycosyl acceptor from the pface through a five-membered ring affording intermediate 247, which upon aqueous workup provides the desired product. The intramolecularity of the reaction combined with delivery through a small ring ensures the excellent levels of stereocontrol.

*
4

P%OR

anorneric activation

*

&;L

(+ &

intramolecular delivery

H20

Hvs-

H

247

Scheme 10-78 Proposed mechanism for intramolecularglycosylation from a tethered acceptor.

The concerted nature of the reaction was further probed by performing the glycosylation in the presence of 1 equiv of methanol [89a, c]. In the case of mixed acetal248, the

10.4 Use of the Temporary Connection in O-glycosylation and Nucleosidation

339

yield of the p 1,6-linked disaccharide 249 was found to be unchanged by the presence of MeOH. However, with acetal 243, the addition of 1 equiv of MeOH resulted in a decrease in the yield of disaccharide 246 which reflects the reduced reactivity of secondary alcohols in sugars. Transfer of MeOH was responsible for the only other product isolated. However, the presence of only the fi-methyl mannopyranoside 250 suggested that this too was formed by intramolecular delivery. Transacetalization with MeOH to form 251 would account for the observance of exclusively this product (Scheme 10-79).

NIS, CHpClp, 1 eq. MeOH,

BnO

0 "C to rt

SEt 248 delivery of 6-OH group unaffected by presence of MeOH

-

249

61% same yield in absence of MeOH

NIS, CHpCIp, 1 eq. MeOH,

*

0"Ctort

SEt

\

transacetalization becomes a competing using less reaction secondary reactive

alcohols

246 11%

243

1g&:y~ 251

i-

intrm;;;laL

z& BnO

OMe

250 40%

Scheme 10-79 The addition of MeOH did not affect the stereospecificity of the glycosylation.

Although the reaction clearly provides a solution to the synthesis of pmannopyranosides, its execution is non-trivial and appreciable optimization is required to achieve good results [89b, c]. This is especially true when preparing more complex oligosaccharides or when low-reactivity secondary hydroxyl sugars are used as glycosyl acceptors. These reactions then require much longer reaction times, allowing product-consuming side reactions to compete with the desired process. Stork and co-workers investigated silyl acetals as the tether-directing group for preparing the difficult Pmannopyranoside linkage [90]. The desired mixed silyl acetal precursor was initially prepared in a stepwise fashion analogous to that described earlier, by

340

10 Use of the Tempomry Connection in Organic Synthesis

first reacting the glycosyl donor with Me,SiCl, to form the chlorodimethylsilyl ether and then adding the glycosyl acceptor to complete formation of the silyl acetal. Oxidation of the phenylthio group with mCPBA provided the sulfoxide which was used in the glycosylation reaction according to the procedure of Kahne et al. (Scheme 10-80) [91]. It was later found that if coupling with a secondary hydroxyl group was desired, the silyl acetal tether could be formed directly by simply mixing an equimolar mixture of the preformed sulfoxide donor and glycosyl acceptor with Me,SiCl,, thus circumventing the need for manipulating the sensitive silyl chloride intermediate [90b].

Si, BnO BnO

SPh

\ I

HO BnO

BnO BnO

BnO

I

SPh

mCPBA, -25 "Cto 0 "C

B-anomer only

BnO "

o

a

BnO B

73% from a-sulfoxide 61% from psulfoxide

n BnO

\ I

,Si-o

f O

M

Brio OMe

*

Tf20, DTBP, CH2C12, 4A ms, -78 "Clo rt

z * g o + BnO

SPh 0

Brio OMe

Scheme 10-80 Linking the mannosyl donor with the glucosyl acceptor via a silyl acetal allows stereospecific Pmannoside formation.

The outcome of the glycosylation is in accordance with the results observed by Barresi and Hindsgaul and is suggestive of intramolecular delivery of the glycosyl donor from the pface. Both a- and Psulfoxides give the same result - the stereochemical outcome is controlled only by the axial orientation of the 2-hydroxyl tether. Using a silyl acetal tether, it was possible to form 0-glucosyl p-mannopyranosides at the 2-, 3-, and 6-positions in good to excellent overall yields [90]. Formation of the 4-0-glucosyl pmannopyranoside 246 by intramolecular delivery, however, proved to be much more problematic and proceeded in a low yield of 12% (this is in contrast to the analogous acetal tether; vide supra) [90b]. The major product from this reaction was found to be the 1,6p-disaccharide 252 in which the silyl acetal bridge remained intact and debenzylation of the 6-hydroxyl group had occurred allowing formation of the observed 1,6-linkage (4% of the a-anomer was also isolated) (Scheme 10-81). A similar observation has been noted by Bols [92d]. Bols has also investigated the use of silyl acetals in intramolecular 0-glycosylation [92]. In early work, he showed that a-glucosides could be readily prepared stereospecifically by attaching the glycosyl acceptor through a dimethylsilyl acetal to the 2-posi-

10.4 Use of the Temporary Connection in 0-glycosylationand Nucleosidation

34 1

tion of phenyl 3,4,6-tri-O-acetyI-l-thio-a-glucopyranoside [92a, c]. Activation of the anomeric group using NIS in the presence of TfOH effected rapid conversion to the corresponding a-glucoside (Scheme 10-82). Several observations were suggestive of intramolecular delivery of the glycosyl acceptor. Stereocontrol was in all cases excellent, with exclusive formation of the a-anomer - analogous intermolecular reactions gave the expected mixture of a-and panomers. The yields and rates of reaction were also not dependent on the steric hindrance of the aglycon; thus octanol and terr-butanol were both transferred with similar efficiency (Scheme 10-82) [92a, c]. Finally, in a competition experiment between intramolecular transfer of tert-butanol and intermolecular reaction with the TMS ether of octanol, the major product was the a-glucoside resulting from addition of the more sterically demanding alcohol.

Tf*O,DTBP, BnO O.,SPh

CHZCIZ-EtzO, -1OO"Ctort

z:*rs B"O

246 12%

\,

BnO BnO

Brio OMe

OMe 252 82%

Scheme 10-81 Formation of the /%1,4-linkageusing a silyl acetal tether proved problematic.

Scheme 10-82 a-Glucosidation is possible through intramolecular transfer.

Silyl acetals were also employed in the preparation of disaccharides containing a-gluco and a-galacto linkages [92b, d]. The conditions used in the glycosylation were found to be important in achieving the desired coupling products (Scheme 10-83). When silyl acetal253 was treated with NIS in the presence of TfOH, only 19%of the desired a-glucoside 254 was isolated; the major product resulted from cleavage of the tether. Clearly

342

10 Use ofthe Temporary Connection in Organic Synthesis

the presence of TfOH, required to effect reaction on such a deactivated glycosyl donor, was cleaving the tether more rapidly. Fortunately it was found that by changing the solvent from CH2Cl, to the more polar nitromethane, heating at 100 "C,allowed glycosylation to proceed without the need for acid and provided 254 in very good yield and as a single anomer [92b, d].

NIS, MeN02, PhS

I 253

OMe

100 "C, 74% 254

OMe

Scheme 10-83 The use of nitromethane circumvents the need for TfOH and allows the forma-

tion of disaccharide 254.

In previous studies, including those of Stork and Hindsgaul [89, 901, the glycosyl acceptor was tethered to the 2-hydroxyl group of the donor. The short tether length (three atoms between reacting centers) and intramolecularity of the reaction ensures complete stereocontrol. Bols and Hansen have also investigated the use of more remote hydroxyl centers for tethering a simple aglycon, octan-1-01, to the glycosyl donor [93]. Thioglucosides 255,256, and 257 were prepared uneventfully and subjected to glycosylation using NIS as activator in nitromethane. The results are outlined in Scheme 10-84. When the aglycon was attached to the 3-hydroxyl group, reaction was not stereoselective, affording a 1 :4 mixture of alp anomers in a low yield of 22%. Tethering to the 4-position proved more successful, providing the a-glucoside 258 exclusively, in 45% yield. The stereoselectivity of this reaction is interesting since it requires a conformational change in which the silyl linker assumes an axial position to allow delivery of the aglycon to the anomeric position. Finally, attaching the aglycon to the 6-position provided the pglucoside 259 with complete stereocontrol although the major product from this reaction was tribenzyl-levoglucosan 260 (Scheme 10-84). This very brief study demonstrates that more remote tethers can be used for stereoselective glycosylation although yields are usually poorer and levels of stereocontrol not always good. The use of the so-called aglycon delivery method provides the most reliable method of forming the Pmannoside linkage. However, the tethers discussed so far are fairly limited in their compatibility with other standard manipulations carried out during oligosaccharide synthesis. Ogawa and co-workers have recently introduced an alternative which possesses a number of advantages over the previously investigated silyl acetal and dimethylacetal tethers [94]. They realized that a p-methoxybenzyl (PMB) ether, a commonly used protecting group in oligosaccharide chemistry, could be used as a latent tethering unit. This protecting group is readily cleaved under oxidative conditions by treatment with DDQ or CAN. If a glycosyl acceptor containing a free hydroxyl group is present during the "deprotection" reaction, then the intermediate oxonium species may be intercepted, resulting in the formation of an acetal tether (Scheme 10-85).Thus, treat-

10.4 Use of the Temporary Connection in 0-glycosylation and Nucleosidation OBn

343

O h

/

/

- \Si,’ NIS, MeNOz,

Bno+o(cH*)sH3 BnO

SPh

25 “C 257

*

BnO Bno&O(CH&CHs OBn 259

+

2:7 70%

OBn OBn 260

Scheme 10-84 Remote tethers are less useful for stereoselectiveintramolecular glycosylation.

ing the 2-PMB-protected mannosyl donor 261 with DDQ in the presence of molecular sieves and the glucosamine acceptor 262, tethered intermediate 263 could be formed. Without the need for isolation, activation of the anomeric linkage with silver triflate/tin(II) chloride provided exclusively the p-1,4-mannopyranoside 264 in 40% yield (Scheme 10-85). A variety of solvents were investigated, and of those surveyed only toluene proved to be unsuitable; reaction in this case was sluggish, probably owing to poor stabilization of the cationic intermediate, and gave a mixture of products. This methodology has been applied to a number of important oligosaccharides, including the core pentasaccharide structure of asparagine-linked glycoproteins shown in Figure 10-6 [94b, fl. Glycosylation is not restricted to the use of anomeric fluorides as glycosyl donors; thioglycosides have also been used [94b, c]. The ,&mannosidereaction has recently been optimized and, with a suitable choice of protecting groups, can be performed in yields around 80% [94e]. The application of solid supports in oligosaccharide synthesis has received much attention in recent years [95], one of the main reasons for this being the facilitated purification of the products. Ito and Ogawa have shown that their intramolecular aglycon delivery strategy can be applied to a polymer-supported system in a novel approach to “clean” glycosylation [94d]. A modified PMB ether protecting group was used to attach a mannosyl thioglycoside to a poiy(ethy1ene glycol) (PEG) support. Treatment of 265 with DDQ in the presence of an excess of the glycosyl acceptor 266 allowed tether formation as before. The tethered intermediate now attached to PEG was then precipitated with terr-butyl methyl ether, and washing allowed facile purification and recovery of the

10 Use ($the Temporary Connection in Organic Synthesis

344

+.

OMe

& : BnO

OBn DDQ, CH2C12. F

4A ms

L

BnO

F

261

40%

L

NPhth 262

1

,OM€

263

Scheme 10-85 PMannosides may be produced by intramolecular aglycon delivery using a PMB acetal tether.

excess glycosyl acceptor. Redissolution in 1,2-dichloroethane and activation of the thioglycoside with MeOTf/MeSSMe in the presence of 4-Me-DTBP effected glycosylation. By using a polymer-bound tether, only the product resulting from tether cleavage - i.e., the desired disaccharide 267 - would enter the solution phase, leaving by-products resulting from hydrolysis or elimination of the thio group still attached to the PEG support. Simple aqueous workup and facile chromatographic purification provided the desired disaccharide 267 in good yield (Scheme 10-86). Fructofuranosides are widespread in nature and, with few exceptions, are plinked. The use of the PMB intramolecular aglycon delivery strategy developed by Ogawa and Ito has also been successfully applied to the stereospecific synthesis of PD-fructofuranosides by Krog-Jensen and Oscarson [96]. They showed that preparation of the PMB acetal was possible with the PMB ether attached to either the glycosyl donor 268 or acceptor 269. Further iniprovements to this step were made by adding the DDQ solution dropwise to a solution of the PMB ether and free alcohol over 2 h and by quenching the reaction by the addition of Et,N. Of a range of different activating agents investigated, dimethyl(methy1thio)sulfonium trifluoromethanesulfonate (DMTST), iodonium collidine perchlorate (IDCP) and iodonium collidine triflate (IDCT) all proved superior to the conditions originally reported by Ogawa. NIS was also useful, although in this case the relatively nucleophilic succinimide anion intercepted the intermediate cationic intermediate and provided the corresponding N,O-acetal product 270, albeit in good yield and with complete @selectivity at the new anomeric linkage (Scheme 10-87).

345

10.4 Use oj‘the Temporary Connection in O-glycosylation and Nucleosidation O

V

O

d

OPEGM

e

O

y

O

0

a

O

M

e

0 i) acetal formation

+

265

BnO

ii) precipitate PEG iii) wash and recover excess acceptor ~

OBn

266 2.6 eq.

SMe

glycosylation by-products remain on PEG support

OBn

TBDPSO

50% 267

OBn

desired disaccharide released into solution

Scheme 10-86 Use of a polymer-supported glycosyl donor provides a “clean” approach to

mannosylation.

p

The use of bis-ester tethers in remote intramolecular glycosylation has been investigated by a number of groups. In contrast to the short tethers used by Stork, Hindsgaul, and Ogawa, these more remote tethers provide a much less predictable outcome and as a result they remain less synthetically useful. Another difference between the short tethers and remote bis-ester tethers is that the reacting alcohol functionality is not masked in the tether but is already free to react as soon as the anomeric center is activated. Valverde and co-workers have investigated the use of bis-ester tethers derived from phthalic and succinic acids in remote glycosylation reactions [97]. Formation of the tether was achieved in a stepwise fashion from phthalic or succinic anhydride. For example, reaction of phenyl 2,3,4-0-acetyl- 1-thio-P~-glucopyranosidewith phthalic anhydride, followed by treatment of the intermediate carboxylic acid with SOCl,, generated the acid chloride 271. This was then reacted with glycosyl acceptor 272 with complete regioselectivity at the 2-OH position using a known procedure [98], providing the tethered glycosylation precursor 273. The presence of two free hydroxyl groups in the acceptor sugar now presents the further complication of regiocontroi in addition to that of stereocontrol at the anomeric linkage. Reaction at the 3-OH position would provide a 13-membered ring while a 14-membered macrocycle would result from glycosylation using the 4-OH group as the nucleophile. It was hoped that geometrical constraints imposed in the different reacting cyclic T. S.s would control both the regio- and the stereochemical outcome of the reaction. Activation of the thioglycoside 273 with NIS/TfOH at room temperature effected rapid reaction, providing a single stereo- and regioisomer 274 in excellent yield (Scheme 10-88). The use of a more flexible succinyl tether gave the same result, albeit in slightly diminished yield; reaction occurred exclusively at the 3-hydrox-

346

I0 Use of the Temporary Connection in Organic Synthesis

OMe

270

57% using 268

77% using 268

53% using 269

53% using 269

Scheme 10-87 A PMB acetal tether can be used to prepare pfructofuranosides.

yl position providing the p-anomer 275 (Scheme 10-88).Changing the protecting groups on the glycosyl donor from acetates to ethers, which cannot participate in the reaction (methyl or benzyl), provided the same regiochemical outcome but stereocontrol was reduced, with up to 15% of the a-anomer also being isolated. Nevertheless, the fact that the major product was the 3-p-glycoside suggests that the tether remains instrumental in governing the outcome of the reaction. By changing the anchoring sites of the bis-ester template, it is possible to reverse completely the regioselectivity of the coupling [97b]. For example, when a phthalyl tether was used to link the 2-OH of a glucosyl acceptor to the 6-OH of a mannosyl donor to

10.4 Use of the Temporary Connection in O-glycosylation and Nucleosidation

347

OTBDPS

272

271

A c O b S p h

microwave * irradiation, BuPSnO

NIS I TfOH,

___)

ACO

OAc

rl

___

273

274

80%

p-anomer only

OTBDPS

NIS /TfOH.

rt 275 65% p-anomer only

Scheme 10-88 Use of phthalyl and succinyl ester tethers provides another approach to regioand stereocontrolled glycosylation.

form 276, glycosylation proceeded with complete regioselectivity (and stereoselectively), with reaction occurring exclusively at the 3-OH. Alternatively, if the glucosyl acceptor was tethered through the 6-OH affording precursor 277, treatment with NIS/TfOH provided exclusively the regioisomeric 4’42glycoside 278 (Scheme 10-89). Ziegler and co-workers have also investigated the use of phthalyl, succinyl, and malonyl ester tethers in a wide variety of intramolecular glycosylation reactions although they have only concentrated on controlling the stereochemical outcome of the glycosylation reaction [99]. They used this approach to prepare PL-rhamnoside linkages [99a], which, like PD-mannosides, are notoriously difficult to prepare owing to the presence of an axially oriented oxygen at C-(2). A number of ethylthio and phenylthio a-rhamnosyl donors were linked through the 2-OH to the 3-OH of a glucosyl acceptor by a phthalyl, succinyl, or malonyl spacer group. The prearranged saccharides were then treated with a variety of activators, in a range of solvents and at different temperatures, affording good to excellent yields of the glycosylation product as a mixture of a-and panomers. The best results were obtained with the rhamnosyl derivative 279,which uses a flexible suc-

I0 Use of the TernporarjJConnection in Organic Synthesis

348

OTBDPS

NIS / TfOH. 76%

276

SPh glycosylation exclusively at 3-position

NIS / TfOH, 72%

2n

glycosylation exclusively at 4-position

Scheme 10-89 Different anchoring sites can be used to vary the regioselectiveoutcome in cycloglycosylation.

cinyl spacer: activation of the anomeric position with NIS/TMSOTf in acetonitrile at -30°C for 10 min provided a 16:84 mixture of alp anomers 280 and 281 in excellent overall yield (Scheme 10-90).

NIS. TMSOTf.

*

BnO

MeCN. -30 “C, 10 min. 90%

0 279

280

O

16:84

261

Scheme 10-90 Careful choice of tether and reaction conditions allows the formation of a PLrhamnoside.

The presence of a 2-acyl group in the rhamnosyl donor would be expected to give rise

to high a-selectivity in the product. The solvent is also very important in the reaction

outcome - only when MeCN is used does the reaction show any signs of useful stereocontrol in favor of the desired product. Force-field calculations (using Insight 11) on the

10.4 Use of the Temporarjl Connection in 0-glycosylation and Nucleosidation

349

two products revealed that the desired panomer was around 10 kcal mol-' more stable than the a-anomer analog. This is, at least in part, a result of a more favorable staggered conformation of the methylene groups in the succinyl tether found in the panomer. This and other investigations into the synthesis of difficult glycosidic linkages illustrate that the use of a bis-ester tether offers distinct advantages over the corresponding intermolecular reaction in terms of improved levels of stereocontrol. However, to obtain the best results requires appreciable optimization involving variation of the length and type of tether, in addition to the anchoring sites to the reacting sugars - very small conformational changes in a large cyclic T. s. can have a profound effect on the stereochemical outcome of the reaction. Although the reaction outcome is clearly influenced by the nature of the bis-ester bridging group, other effects such as solvent, method of activation, and temperature are crucial in controlling the reaction. Takahashi and co-workers have used molecular mechanics calculations in designing a suitable tether for a synthesis of the branched trisaccharide 282 [ 1003. It was envisaged that appropriate tethering of the glycosyl fluoride donor to the disaccharide acceptor, which has three sites for reaction, would impart a high degree of regio- and stereocontrol in the key glycosylation reaction. Succinyl and phthalyl tethers attached in both cases to the 6-position of the disaccharide acceptor and to the 2- and 3-positions of the fluoride glycosyl donor provided four possible glycosylation precursors. Monte Carlo (MC) conformational searches were performed on all isomers generating a number of low-energy conformations for each isomer. These were further minimized using the AMBER forcefield implemented in MacroModel. Subsequent analysis of a Boltzmann distribution of all these conformers at 25 "C revealed that the anomeric carbon of the glycosyl donor was close to the 4-OH group of the glycosyl acceptor in 90% of the total conformer population. In particular, isomer 283 seemed to possess the most favorable arrangement (in the ground state) with a distance of 3.59 A between the C(4)-oxygen atom and the reacting anomeric carbon atom. Similar conformational analysis and energy minimization of the cyclized products revealed that this precursor linked by a phthalyl ester between the 2-OH position of the donor and the 6-position of the acceptor also provided the most stable product. With these results in hand, the isomer predicted to be most favorable for cyclization was prepared and subjected to glycosylation. The expected trisaccharide 284, where glycosylation had indeed proceeded on the 4-OH group affording a plinkage, was isolated in 37% yield. The analogous intermolecular reaction was also investigated to provide a measure of the utility of the tether. This produced a mixture of trisaccharides in poor yield, where reaction had occurred at the 2-OH and 3-OH positions only. This clearly demonstrates that intramolecularizationusing a tether not only improves the yield, but also ensures that reaction occurs exclusively at the least reactive 4-OH group (Scheme 10-91). Huchel and Schmidt have used a remote glycosylation strategy to prepare the cellobioside 285 [loll. In this case, they utilized a bis-ether linkage prepared from a,a'-dibromo-rn-xylene to pre-organize the glycosyl donor and acceptor. It was found that a linkage through the 6-position of the donor and the 3-position of the acceptor gave the best result. Treatment of 286 with NIS/TMSOTf provided the 14-membered macrocycle disaccharide 287 in excellent yield as a single anomer (Scheme 10-92). Global debenzylation followed by peracetylation provided the desired cellobioside 285.

350

10 Use of the Temporary Connection in Organic Synthesis OAc

succinyl I phthalyl

i) MC conlonational search

& + I

ii) AMBER minimization 4possible glycosylation precursors

'ri

1

9eF CpzHfC12.AgOTi. CH2C12,4A ms, 37%

I

282

I

283

284

Scheme 10-91 Molecular mechanics can be used to design tethers for remote glycosylation.

206

187

celiobioside 285

Scheme 10-92 A bis-ether tether was used in a stereoselective synthesis of cellobioside 285.

Remote glycosylation strategies using bis-ester and ether tethering strategies can provide useful levels of regio- and stereocontrol which are not always possible using analogous intermolecular reactions. Levels of stereocontrol are not always as high as when the shorter tethers discussed earlier are used. Nevertheless, the stereoselective synthesis of PL-rhamnoside and PD-mannoside linkages is illustrative of the potential of this approach. The tethered precursors are relatively easy to prepare, stable to the glycosylation conditions, and readily varied, allowing fine tuning of the reactive conformation for improving or varying selectivity. However, the major drawback with this approach is the difficulty in predicting the outcome of the reaction - the much larger cyclic T. S.s require fairly complicated molecular mechanics computational studies for understanding favored reactive conformations.

10.4 Use of the Temporary Connection in O-glycosylation and Nucleosidation

35 1

All the examples of tether-directed intramolecular glycosylation discussed so far have involved connecting the two reacting partners through the hydroxyl substituents around the sugar rings. An alternative site of attachment for the glycosyl acceptor is through the anomeric leaving group of the donor [102-1041. This method of glycosylation has received less attention but is potentially more versatile. Since the glycosyl donor leaving group is also the glycosyl acceptor, the need for preparing potentially unstable donor precursors is circumvented. Furthermore, the protecting group strategy is less affected by the need to form a tether. Ideally, the reaction would proceed stereospecifically through an S,i-type mechanism, where the configuration of the starting material would dictate that in the product glycoside. The concept is outlined in Scheme 10-93.

A = glycosyl acceptor

Scheme 10-93 Leaving group-based intramolecular glycoside bond formation is an attractive route to stereoselective glycosylation.

Behrendt and Schmidt provided an early example of this approach [102]. Reaction of 0-glycosyl trichloroacetimidates 288 and 289 with cyclohexanecarboxylic acid proceeded with inversion of configuration, providing the corresponding anomeric carboxylic esters 290 and 291, respectively. Subsequent aldol reaction with benzaldehyde provided the Phydroxy carboxylates 292 and 293 as a mixture of diastereoisomers. When /%configured 292 was reacted with the 6-O-triflate of methyl 2,3,4-tri-0-benzyl-a-~-glucopyranoside in the presence of NaH and 15-crown-5 at 0 "C,the disaccharide 294 was isolated in 68% yield as a 10 : 1 mixture of p/a anomers. Reaction of the a-configured precursor 293 under similar conditions but at -30 "C,provided 295 in 81% yield as a 1 :2 mixture of p/a anomers in addition to small quantities of products arising from retroaldolization and O-alkylation (Scheme 10-94). The isolation of a plactone product 296 suggests a possible reaction mechanism (Scheme 10-95). Reaction of NaH/lS-crown-5 with the aldol product generates the corresponding alkoxide 297. As a result of steric crowding, this is not directly alkylated instead, cyclization onto the ester functionality and trapping of this alkoxide provides an intermediate orthoester 298. Relief of strain by 1,3-glycosyl transfer then furnishes the observed products (Scheme 10-95). It is also interesting to note that the stereoselectivity in the reaction depends on the configuration of the starting material, as is desirable in this type of transformation: thus the Pcarboxylate precursor provides the Panomer prefe-

352

10 Use ojthe Temporary Connection in Organic Synthesis BnO CGH~IC~ZH

BnO

BnO

LDA, PhCHO, THF, -80"C BnO

BnO

Brio OMe*

NaH,15-crown-5, 294 B:a1O:l

Bn0AMe

B BnO n O a o + o

CHzC12,O "C, 68%

BnoHO.&J 292

Ph

*o: :B BnO BnOO 291

--c2 0

LDA, PhCHO, THF, -80"C

."T* BnO

Brio OMe , + NaH, 15-crown-5, CHzCI2. -30 "C, 81%

293 " O Y L a Ph

Scheme 10-94 Leaving group-based intramolecular glycosylation.

rentially, while the a-isomer generates the a-glycoside preferentially. These ratios exhibit a temperature dependency; they are improved at low temperature. An alternative linker which can serve as both a leaving group and a latent glycosyl acceptor is a mixed carbonate [103]. In this case, suitable activation with a Lewis acid causes extrusion of carbon dioxide and formation of the reactive glycosyl acceptor, which can then be trapped by the glycosyl donor. The mixed carbonate precursor 299 for this decarboxylative glycosylation strategy was prepared as a mixture of stereoisomers

10.4 Use ojthe Temporary Connection in 0-glycosylution und Nucleosidation

353

BnO

297

298

Ph

Ph

1,3-glycosyl transfer

Ph

BnO

296

major product

Scheme 10-95 Formation of an orthoester followed by 1,3-glycosyl transfer are possible steps in the mechanism.

in a stepwise fashion by treating the glycosyl donor 300 with the activated carbonate 301 (Scheme 10-96).Of the Lewis acid activation systems which were examined, TMSOTf, SnC14/AgC104,and Cp2HfC12/AgC104proved to be most useful. However, the results suggest that the tether has relatively little effect on the stereochemical outcome of the reaction, which is more dependent on the structure of the glycosyl donor, the solvent, and the temperature. This apparent lack of tether-directing stereocontrol in the decarboxylative glycosylation strategy highlights an important caveat in all such reactions where the nucleophile is generated as the tether is being broken. The tether is only likely to provide good levels of stereocontrol if the bond-breaking and bond-forming events proceed at a very similar time. This seems to be the case in the short acetal and silyl acetal tethers of Stork, Hindsgaul, and Bols (vide supra). If the reaction is non-concerted, it more closely resembles an

BnO

BnO Ho*o ; : 3€ BnO

+

BnO 300

~"0% BnO

NaH.THF

TMSOTf, mesitylene,

~

BnO

BnoOMe 301

299

0 "C

BnO 78% a:P 1 6 8 4 (toluene a:P 32.68)

Scheme 10-96 Formation of a mixed carbonate allows a decarboxylative glycosylation pathway.

354

10 Use of the Temporary Connection in Organic Synthesis

intermolecular process and as such will be affected by the usual external variables such as solvent and mode of activation. Indeed, Scheffler and Schmidt have performed the appropriate competition experiments, suggesting that the decarboxylative glycosylation procedure, at least in the case of silyl triflate activation, proceeds through an intermolecular, non-concerted pathway [ 1051, and as such, this strategy shows little or no advantage over more conventional intermolecular glycosylation protocols. In summary, the increasing interest in oligosaccharides necessitates improved methods for their synthesis in diastereoisomerically pure form. One strategy which has been investigated for controlling the outcome of the glycosylation reaction is the use of a temporary connection. This has provided some of the best synthetic routes to date for the synthesis of difficult linkages such as PL-rhamnosides and p-D-mannosides. However, there remains appreciable scope for improvement. The silyl acetal and acetal tethering methodology developed primarily by Stork, Hindsgaul, and Bols become much less efficient when they are applied to the synthesis of anything larger than a disaccharide and then require appreciable optimization. Ogawa's PMB-acetals are perhaps the most promising tethers in this family. The remote glycosylation strategies using bis-esters and ethers are more robust but the lack of simple rules for predicting the stereochemical outcome of the glycosylation event hinder their more widespread use. Leaving group-based glycosylation is an attractive alternative to the substituent tethers. However, ensuring a concerted reaction is paramount to obtaining high levels of stereocontrol in these reactions - for the most part, this problem has not been solved.

10.4.2 Directed Nucleosidations One of the most frequent ways of preparing nucleosides is to use the Vorbriiggen modification of the Hilbert-Johnson reaction in which a silylated base reacts with an activated sugar to form the nucleoside linkage [106]. The stereoselectivity of this process is highly dependent on the substitution pattern at the 2'-position of the sugar. In the case of ribosides containing a 2'-a-acyloxy group, neighboring group participation ensures that the panomer is formed almost exclusively. However, in the absence of this functionality, nucleosidation is much less stereoselective and a mixture of a- and panomers is usually obtained. Modified nucleosides have been shown to exhibit a range of biological properties and are attracting increasing attention as therapeutic agents. Efficient methods for the stereoselective synthesis of these compounds, in particular controlling the anomeric linkage, are therefore desirable. The groups of Jung [lo71 and Sugimura [lo81 have both addressed the problem of anomeric selectivity in the preparation of 2'-deoxyribonucleosides by intramolecular delivery of the base through a temporary attachment to the 5'position of the riboside. The geometry of the tetrahydrofuran ring then ensures that the base is delivered exclusively to the @face, providing the desired panomer after hydrolysis of the tether (Scheme 10-97). Jung and Castro prepared 2'-deoxyuridine 302 using this strategy [107]. Reaction of the potassium salt of ribal303 with 2-methylthiopyrimidone 304 incorporated the base.

10.5 Tether-mediated Nucleophile Delivery

355

Vorbrijggen protocol utilizes neighboring group participationto achieve stereocontrol in nucleosidation

“kc

TMS

TMSOTf orSnCl activatio47

Ro

P-attack

~

0

RO OAc

px0

activation

P

RO

X = leaving group R = protecting group

s

hydrolysis

____t

RO

RO

Jung and Sugimura’s approach to stereoselective nucleosidation of 2deoxyribonucleosides relies on intramolecular delivery of the base

Scheme 10-97 Intramolecular delivery of the nucleoside base provides a solution to the problem of stereocontrol in 2’-deoxyribonucleosides.

Subsequent hydration of the enol ether followed by BOM-deprotection and formation of the anomeric acetate provided the nucleosidation precursor 305. In situ silylation of the pyrimidone and activation of the anomeric group with TMSOTf gave the desired 2’deoxy-3’-O-methyluridine302 in moderate yield after basic hydrolysis of the tether with no contaminating a-anomer (Scheme 10-98).A similar strategy was used by Sujino and Sugimura to prepare similar compounds [log].

10.5 Tether-mediated Nucleophile Delivery The tether directing strategies for C-and O-glycosylation are one subset of a much wider area of using the temporary connection for controlling the regio- and stereochemical outcome in the reaction of nucleophiles with an electrophilic substrate. Some examples of this form of tether-mediated synthesis will be illustrated with some applications to natural product synthesis [109].

356

HO

10 Use @-the Temporary Connection in Organic Synthesis

A

1N NaOH

TMSOTf, MeCN, -78 to It

c -

c -

OMe

OMe

-1

302 43% from 305

Scheme 10-98 Intramolecular Vorbriiggen coupling allows stereoselective synthesis of deoxyribonucleosides.

p2’-

10.5.1 Synthesis of (+)-Hydantocidin The spironucleoside hydantocidin 306 exhibits a number of interesting properties, including herbicidal and plant growth regulatory activities. All possible diastereoisomers have been synthesized and only the naturally occurring isomer was shown to display significant biological activity [ 1101. The most challenging task in a synthesis of 306 was correct installation of the stereochemistry at the anomeric center. Furthermore, since the a-nitrogen is thermodynamically more stable than the pisomer, it was not possible to rely on thermodynamic equilibration to install this key stereocenter. In Chemla’s approach, it was decided to tether a suitable nitrogen nucleophile to the 6position of the sugar moiety to ensure &facial selectivity in the key nucleosidation-type reaction [ 1 1 13. Hydroxylamine 307, readily prepared from D-fructose, was treated with p-methoxybenzyl isocyanide to afford the corresponding urea derivative 308 in excellent yield (Scheme 10-99).Treatment with the Lewis acid TMSOTf effected smooth cyclization to isoxazolidine 309, installing the correct stereochemistry at the anomeric position. Oxidation and removal of the PMB protecting group generated the tricyclic isoxazolidine hydantocidin 310, which just required cleavage of the hydroxylamine tether and removal of the acetonide protecting group to reveal the desired compound. A number of proved reducing agents were examined for cleaving the N - 0 bond, of which MO(CO)~ to be the reagent of choice. Acid-catalyzed deprotection of the acetonide then provided hydantocidin 306.

10.5 Tether-mediated Nucleovhile Delivery

357

PMBHN

L O

I

309

308

307

i) NapCr07,H2S04.

acetone

ii) CAN, MeCN-H20, 70% (2 steps)

HO

HO

HO

OH0

0 "C, quant.

MeCN-H20,

hydantocidin

306

310

Scheme 10-99 Intramolecular delivery of a nitrogen nucleophile provides the correct stereochemistry at the anomenc position for a synthesis of hydantocidin.

10.5.2 Synthesis of Lincomycin Knapp and Kukkola have reported a synthesis of the antibiotic lincomycin 311 (Scheme 10-100) [112]. Earlier synthetic approaches to this molecule had revealed that the C(6) position was very hindered precluding efficient incorporation of the amino functionality via conventional intermolecular protocols. To circumvent this problem they chose to deliver a nitrogen nucleophile intramolecularly from a tether at C(4). It was anticipated that epoxide opening would proceed regioselectively in a 6-ex0 manner, incorporating the desired stereochemistry at both C(6) and C(7)positions. To this end, epoxy alcohol 312 was synthesized in good overall yield from commercially available methyl OI-Dgalactopyranoside. After some experimentation, treatment of the sodium alkoxide of 312 with dimethylcyanamide created the isourea tether which underwent spontaneous, stereospecific epoxide ring opening furnishing, after rearrangement, oxazoline 313 in 95% yield. Benzylation of the 4-OHand subsequent hydrolysis of the tether generated amino alcohol 314, which was subsequently converted into lincomycin 311.

10.5.3 IntramolecularAllylation Use in the Synthesis of llicyclic P-Lactam Antibiotics The stereoselective allylation of aldehydes is one of the most important, and intensively investigated, reactions in synthetic chemistry [ 1131. Nowadays, one of the most efficient

358

10 Use of the Temporan, Connection in Ornanic Svnthesis NMe2

04 BnO

BnO 312

L

I

313

J

OMe

i ) BnBr, DMF

ii) KOH, (CHpOH)2

f

steps

BnO

HO SMe

BnO 314

OMe

lincomycin 311

Scheme 10-100 Intramolecular delivery of a nitrogen nucleophile allows stereospecific incorporation of the amino functionality at the sterically hindered C(6) position.

ways of carrying out this transformation is to use a chiral Lewis acid in the presence of an allylstannane [ 1141, or to use chiral ligands on the allyl metal reagent [ 1151. However, prior to the developmentof these methodologies, substrate control was widely used to achieve asymmetric induction in the reaction. Reetz and co-workers have made a number of important studies into the effect of a-and pstereocenters on the addition of nucleophiles to carbonyl functionality.In one such investigation, the sense of 1,3-asymrnetric induction using a tethered allylsilane was shown to be highly dependent on the choice of Lewis acid [ 1161. They found that reaction with TiCI, proceeded in excellent diastereoselectivity, providing predominantly the syn product 315. This observation is in agreement with an intramoleculartransfer of the allyl nucleophile through an eight-membered T. S. in which the psilyl ether and aldehyde form a chelated structure outlined in Scheme 10-101. The intramolecularity of the reaction was proved by a series of crossover experiments. The result is complementary to that obtained using SnC1, as the Lewis acid, where the anti diol product predominates. This reaction was shown to be an intermolecular process. Allylation using tethered nucleophiles has been investigated by other groups and has been shown to typically exhibit excellent levels of stereocontrol [117], which in some cases are complementary to those obtained in the corresponding intermolecular process. A Glaxo group used such an approach in the synthesis of a key intermediate for the preparation of tricyclic plactam antibiotics [ 1181.

10.5 Tether-mediated Nucleophile Delivery

'li

0'

R

_/= 0

AJH

OH OH

Ti& CH&,

-78 "C

359

*

R=Me R = BU

major product 315 R = Me, syn:anti 92:8, (70%) R = Bu, syn:anti 90:10, (80%)

Scheme 10-101 Intramolecular allylation provides the complementary stereochemical result to

the analogous intermolecular process.

Preparation of the temporary connection was achieved by reaction of acetoxy lactam 316 with allyl(ch1oro)silane 317, generating the N-silyl species 318. Exposure to TMSOTf at 0°C effected in situ formation of the N-acyliminium species, which was trapped by the pendant ally1 nucleophile, providing two out of the possible four diastereoisomeric cyclized products, 319 and 320 in a 4:l ratio (Scheme 10-102). Formation of the two products may be accounted for by cyclic T. S.s where addition occurs onto the re face of the azetinone, anti to the sterically demanding silyl ether group through a chair-like or boat-like conformation.

10.5.4 Synthesis of Corticosteroids A variety of different covalent tethering strategies have been used in stereo- and regioselective manipulations of the side chains of steroids. Livingston et al. utilized a temporary connection for nucleophilic delivery in a facile synthesis of corticosteroids from readily available androst-4-ene-3,17-dione321 [119]. Reaction of 321 with KCN proceeded chemoselectively at the 17-ketone, providing a mixture of cyanohydrins, from which the 17pcyanohydrin 322 could be obtained after equilibration and recrystallization. Conversion to the (chloromethy1)silyl ether 323 provided the additional carbon required for homologation. Treatment of 323 with LDA effected deprotonation of the chloromethyl group and cyclization onto the nitrile providing 2 1-chloroketone 324 in 93% yield from 323 after acidic workup (Scheme 10-103). Reductive dehalogenation or nucleophilic displacement of the chloride with KOAc afforded 17a-hydroxyprogesterone 325 and cortexolone acetate 326 respectively, both in quantitative yield. Although the homologation may be achieved using standard intermolecular reactions, the described sequence is noteworthy in that there is no need to protect either alcohol or 3-keto functionality.

10.5.5 Synthesis of (-)-a-Kainic Acid Kainic acid 327 exhibits an array of biological properties, including insecticidal, antithelmic, and neuroexcitatory activity. One of the challenging aspects to the synthesis of

360

I0 Use of the Temporary Connection in Organic Synthesis

OTBS

TMSOTf, MeCN, 0 "C then Et3N, MeOH

T.S.s not shown

O R reboat

319

4:1

50%

320

Scheme 10-102 Tether-directed allylation provides a diastereoselective route to precursors in the synthesis of tricyclic plactam antibiotics.

such a trisubstituted pyrrolidine is the formation of the cis relationship between the C(3) and C(4) positions. Bachi and Melman showed that a potential precursor 328 could be prepared in enantioselective form [120]. To complete the synthesis of kainic acid, it just remained to carry out a formal SN2substitution of the tosylate with an acetic acid residue. Attempts to do this using an intermolecular reaction were hampered by the steric hindrance at the reacting site and facile elimination involving the particularly acidic hydrogen at C(2). To overcome these problems, an intramolecular nucleophile delivery strategy was devised (Scheme 10-104) [120]. Addition of the sulfenyl chloride 329 derived from methyl mercaptoacetate to the isopropenyl group proceeded with complete regio- and stereocontrol affording 330, and subsequent oxidation with mCPBA provided the corresponding sulfone 331. The use of a sulfone tether instead of the simple sulfide

10.6 Silican-tethered Ene Cvclization

321

322

CICH2SiMe2CL-D Et3N, DMAP, THF

,

36 1

323

17a-hydroxyprogesterone 325

OAc

cortexolone acetate 326

Scheme 10-103 Intramolecular nucleophile delivery provides an efficient route to biologically important corticosteroids.

was found to be necessary since, under the basic conditions used to prepare the enolate nucleophile, elimination of the sulfenyl chloride to the isopropenyl precursor 328 was observed. Additional advantages of the sulfone tether include its increased stability and a more acidic a-proton which allows the use of milder reaction conditions to generate the enolate nucleophile. The desired stereospecific intramolecular substitution was achieved in good yield upon treatment of 331 with potassium methoxide in THE Samarium diiodide proved to be the reagent of choice for cleaving the temporary connection, and after global deprotection provided kainic acid 327.

10.6 Silicon-tethered Ene Cyclization Robertson and co-workers have investigated a Type I1 intramolecular version of the ene reaction in which the reacting partners, an oiefin possessing an ailylic hydrogen and an aldehyde, are tethered at an internal site [121]. In analogy with intramolecular variants in which the reactants are linked through an all-carbon tether [122], this reaction was antic-

10 Use of the Temporary Connection in Organic Synthesis

362

?O2Me

79%

mCPBA,

*

92%

*

BOC

BOC

BOC

320

330

331

MeOK, THF, 75%

327 kentc acid

Scheme 10-184 Synthesis of kainic acid in which Bachi and Melman use- intramolecular nucleophile delivery.

ipated to proceed with high levels of stereocontrol but with the added advantage of possible cleavage of the silicon bridge at a later stage providing acyclic products. A number of routes were investigated for synthesizing the tethered precursors. The first involved the sequential addition of organometallic nucleophiles to Me,SiCl(NMe,) [121a]. HoweveF, this suffered from a number of drawbacks, including the limited availabi€ity of substituted propionaldehyde homoenolates, and the need to work with the highly reactive aminosilyl chloride. Two new routes have recently been reported [121b]. Both utilize the reaction of propenyllithium with oxasilacyclopentanes which are readily prepared in two ways, namely, a 5-em-trig radical cyclization of (bromomethy1)silyl ethers or intramolecular hydrosilylation of an allylic double bond (Scheme 10-105). Treatment of 332 or 333 with MeAlCl, at -78°C effected reaction providing the cyclized products with excellent levels of stereocontrol. The observed products can be rationalized by invoking the T. S.s outlined in Scheme 10-106 in which the alkyl substituent occupies an equatorial site in the chair conformation and the aldehyde is axial. Reaction was found to be significantly slower than the all-carbon analogs; this may be attributed to the longer C-Si bond length (1.89 A; cf. 1.54 A for C-C) and the reduced ability for silicon to stabilize any buildup of positive charge on the a-carbon atom.

10.6 Silicon-tethered Ene Cvclization

363

47%

332

20%

0

OH

333 42%

Scheme 10-105 Silicon-tetheredene precursors can be prepared in a number of ways. Reagents and conditions: i) 2-propenyllithium,THF, -78 "C; ii) AcC1, rt; iii) (Me0)2CH(CH2),MgBr, THF, rt; iv) pTsOH, a . 'MH,THF, heat; v) Bu3SnH, AIBN, PhH; 'vi) PDC, 4A ms, CH,CI,; vii) [(PPh,),RhCl], 4 ms,THE

5$

332

333

T.S. leading to major product

T.S. leading to major product

296 : c2 79%

<2:>98 76%

Scheme 10-106 Silicon-tetheredene cyclization is highly stereoselective.

364

10 Use of the Temporary Connection in Organic Synthesis

10.7 Intramolecular Hydrosilylation and Related Reactions 10.7.1 Hydrosilylation of Olefins The intramolecular hydrosilylation of terminal olefins and acetylenes is a highly efficient reaction when activated silanes (e.g., HSiCl,) are used in the presence of a metal catalyst (e.g.. [H,PtCl, * 6H20]) 11231. In this case, the reaction is normally highly regioselective with silyl addition proceeding onto the less hindered terminal position. Reaction of trialkylsilanes is appreciably less efficient and often does not proceed at all. Hydrosilylation of internal olefins is also problematic - they exhibit reduced reactivity, allowing side reactions such as catalyst-mediated double bond isomerization to become significant. Furthermore, regioselectivity is also difficult to address. One solution to these problems is to temporarily tether the hydrosilylating reagent to the substrate. The ensuing intramolecular reaction has been shown to be highly efficient and, in certain cases, proceeds with excellent selectivity (intramolecular hydrogermylation [ 1241 and hydroboration 11 251 reactions have also been investigated). Tamao, Ito, and co-workers provided some of the earliest studies [ 1261 and have also investigated the mechanism of the reaction 11271. Treatment of a number of allylic and homoallylic alcohols with (Me2HSi),NH provided the corresponding silyl ethers, which on exposure to 0.1 mol% of Wilkinson's catalyst [(PPh,),RhCl] or hexachloroplatinic acid [H,PtCI, . 6 H,O], underwent hydrosilylation. Subsequent oxidative cleavage of the silyl tether afforded the corresponding diol products in good overall yield (Scheme 10-107). In the case of cyclic systems, e.g., 334, reaction proceeds with excellent stereoand regiocontrol, providing the syn-diol product. Acyclic systems provide more variable results; the outcome is highly dependent on the presence of additional stereocenters and the position and substitution pattern of the reacting olefin. The alkyl substituents on the silicon tether can also influence the stereochemical outcome: use of cyclohexylsilyl hydrides generally provides greater stereoselectivity than in the case of dimethylsilyl analogs [128]. a-Hydroxy enol ethers can be used to provide stereoselective routes to 1,2,3-triols, although in these cases the neutral Karstedt catalyst, [Pt{[(CH,= CH)Me,Si],O),] has to be used to prevent decomposition of the acid-labile substrate 1126~1.Bosnich and co-workers have shown that dihydrosilanes in the presence of an [Rh(Ph,PCH,CH,PPh,)]+ catalyst form the silyl ether tether in situ, providing the cyclized siloxanes directly from the corresponding allylic alcohol [ 1291. A variety of oxidative tether cleavage protocols have also been evaluated which allow regioselective monoprotection of the resulting 1,3-diol products, facilitating differentia-

+

Scheme 10-107 Homoallylic and allylic silyl ethers undergo efficient hydrosilylation. Reagents and conditions: i) (HMe,Si),NH, NH,C1 cat.; ii) [(PPh-,),RhCl] (0.1 mol%), 100 "C; iii) 30% H,O,, NaHCO,, MeOH, THF, 60 "C; iv) [H,PtC16.6H,0] (O.Imol%), rt to 60 "C; v) [Pt{[(CH,=CH)Me,Si],OJ,] (0.1 to 0.5 mol%), 60 "C; vi) 30% H202, 15% KOH, MeOH, THF, rt; vii) (cyclohexyl)chlorosilane,Et,N, DMAP viii) { [Rh(Ph,PCH,CH,PPh,)]+CIO~], Ph,SiH,. Yields are based on the starting alcohols.

365

10.7 Intramolecular Hydrosilylation and Related Reactions

0 -.-o - b,, \ I

OH

oSi. H

OH

ii), iii)

73%a

334

..

\ I

OH OH

iv), iii) Ph

+

OH OH Ph

&

-+ + A iv),iii)

OH OH

OH OH

67%= 6.1 : 1

84%a

syn : anti >99:1

93073 5:l

>25 : 1

Ph

Ph

viii)

>95%

p

h

L

O

1 O%a

6Z0/ea

5.7 : 1

J ,) OH

+

H

10 Use ofthe Temporaty Connection in Organic Synthesis

366

tion of the two alcohol functionalities, and further enhancing the synthetic utility of this hydroxylation protocol (Scheme 10-108) [ 126bl.

9 - 0

I

prn

,,,

O-OMe-

F

t

Prn- prY-l /Si

1 'H

OH

vi) 84%

,i;,

H

OTBS

iv)

58%

Prm OH 0-OMe

vii) 72%

OH OTBS

Scheme 10-108 Different tether cleavage strategies provide access to monoprotected diols. Reagents and conditions: i) MeCOCI, ZnCI, cat., rt; ii) KF, KHCO,, MeOH, THF then 30% H202, rt; iii) MOMCl, CsF, MeCN, rt; iv) 30% H202, KHC03, MeOH, rt to 50 "C; v) DIBALH, Et20,0 "C to 60 "C; vi) TBSCl, Et3N,DMAP, CH2C12;vii) 30% H202,NaHCO,, MeOH, THF, 60 "C.

Curtis and Holmes provided an early display of the synthetic utility of the intramolecular hydrosilylation in their synthesis of the truns-diol 335, an intermediate in their approach to obtusenyne 336 [ 1301. The allylic silyl ether 337 was prepared from the corresponding alcohol using an excess of 1,1,3,3-tetramethyldisilazanein the presence of a catalytic amount of ammonium chloride, and then used without purification. A wide variety of catalysts were investigated with the rhodium complex [Rh(acac)(norbornadiene)] providing the best results in terms of stereoselectivity (trunslcis >95 :5) (Scheme 10-109). Unfortunately, partial loss of the silyl group under the reaction conditions resulted in a moderate yield of the diol product which was not improved when the corresponding diisopropylsilyl ether was used. Hale and Hoveyda have also produced an interesting synthesis of the C(27)-C(33) fragment of the potent immunosuppressant, rapamycin, using the siloxane 338, generated from intramolecular hydrosilylation, in remote acyclic stereocontrol (Scheme 10-110) [ 13I]. Reaction of homoallylic silyl ether 339 gave a 4 : 1 mixture of siloxane products and further manipulation of the major stereoisomer 338 provided Weinreb amide 340. Osmylation of the adjacent double bond not only proceeded with excellent diastereoselectivity, but also with complete rearrangement of the siloxane to an internal position, serving as an efficient method for in situ differentiation of the two newly generated secondary hydroxyl groups. Further reactions provided the correct stereochemical relation of stereocenters found in the C(27)-C(33) fragment of rapamycin. An enantioselective version of the hydrosilylation reaction would greatly extend its synthetic utility. The reaction mechanism of this catalytic asymmetric process has been investigated in great detail and shown to be extremely complicated [ 1321. Nevertheless,

1 yy*""'"i

10.7 Intramolecular Hydrosilylation and Related Reactions

[Rh(acac)(norbornadiene)],,

'

2 mol%, THF, reflux, 16 h

S , i /?'\@oTBDps 'H

-

367

1

Si

\

L

337

i) EDTA, ii) H202, KOH, THF-MeOH

336

335

obtusenyne

61%

>95 : <5

Scheme 10-109 Intramolecular hydrosilylation used by Curtis and Holmes in the synthesis of a key intermediate towards the preparation of obtusenyne.

major product

339

338 0s049"M0 80%

1

340

C(27)-C(33)fragment of rapamycin

Scheme 10-110 Use of a siloxane template in the preparation of the C(27)-C(33) fragment of rapamycin.

a number of catalyst systems have been developed based on rhodium(1) complexes with chiral diphosphines, and excellent levels of enantiocontrol have been achieved. Hydrosilylation of allylic amines proceeds under platinum catalysis with the opposite regioselectivity to their oxygen analogs [ 1331. The intermediate 1-aza-2-silacyclobutanes resulting from a 4-em-trig addition are thermally stable and may be purified by distillation. Alternatively, direct oxidation using the Tamao conditions provides the corresponding 1,2-amino alcohols with excellent syn selectivity (Scheme 10-111).

368

10 Use of the Temporary Connection in Organic Synthesis

Phh.

.

OH iii)

Dh

1

76%a

not isolated

50%a

Scheme 10-111 Pt-catalyzed intramolecular hydrosilylation of allylic amines provides 1,2-amino alcohols. Reagents and conditions: i) BuLi, Me,SiHCI, Et20;ii) [Pt([(CH,=CH)Me2Si],0),], rt; iii) EDTA .2Na, hexane, rt then 30% H202,KF, KHCO,, MeOH, THF, rt.

10.7.2 Hydrosilylation of Acetylenes The attachment of a silyl hydride reagent to homopropargylic alcohols provides a good method for hydrosilylating triple bonds. The temporary attachment again allows regioselective cis hydrosilylation of internal acetylenes with products resulting from an exo-digcyclization mode being observed (Scheme 10-112) [134]. A number of variations have also been reported, including silylformylation [ 1351 and cyanosilylation [ 1361, which also exploit the regio- and stereocontrol from the intramolecular reaction. 0

syn addition 78%a

Scheme 10-112 Intramolecular hydrosilylation of homopropargylic acetylenes proceeds with excellent stereo- and regiocontrol. Reagents and conditions: i) [H,RCI, . 6H20] (0.1 mol%), CH2C12,rt; ii) 30% H,02, KF, KHC03, MeOH, THF, 30 O C ; iii) Br2, 0 “C then KHF,, MeOH, rt. a

Yield based on allylic amine. syn :anti ratio >99:1 in all cases.

10.7 Intramolecular Hvdrosilvlation and Related Reactions

369

10.7.3 Directed Bis-SilylationReactions The bis-silylation of olefins and acetylenes is a potentially desirable reaction on account of the fact that two C-Si bonds are generated in one step. Intramolecular versions would also be attractive. The reaction is analogous to the tethered hydrosilylation described above but has received less attention. One of the major problems which had to be over-

. .

78%

90%

'J-,.

-

92%

,o Me3Si, ,Si-Si P i 'Ph

'

i,

rt

74%

\

M e 3 S > ~ i v , p r vi), vii) 'Ph -80 Ph'

98%

82%

'

.

OAc

,SiMe3

.

.

92%

94%

99%

78%

major stereoisomers shown in all cases; d.s. > 92:8

Scheme 10-113 Intramolecular bis-silylation followed by oxidative tether cleavage provides a

stereoselective route to 1,2,4-tnols. Reagents and conditions: i) Pd(OAc),, lI1,3,3-tetramethylbutyl isocyanide, toluene; ii) TFA then H202, KF, KHCO,, KHF,; iii) Ac,O, Et,N, DMAP; iv) KOrBu, DMSO then H,O,, KF, KHCO,, KHF,; v) TFA then H,O,, TBAF, KHCO,; vi) H202, KF, KHCO,, MeOH, THF; vii) 2-methoxypropene, CSA, acetone; viii) TBAF, THF then H202, KHCO,, MeOH; ix) diimide, EtOH; x) KO'Bu, DMSO then TBAF, KHCO,, H202.

310

I0 Use of the Temporary Connection in Organic Synthesis

come was finding a suitable catalyst system. Ito and co-workers made the major breakthrough by finding that Pd(OAc), in the presence of an excess (with respect to Pd) of I , 1,3,3-tetramethylbutyIisocyanide was a highly efficient catalyst system for the bis-silylation of homoallylic olefins and acetylenes [ 1371. Although the precise nature of the active species is not known, it is most probably a palladium(0) species with coordinated isocyanide groups since no reaction was observed in the absence of the isocyanide. A variety of disilanyl ethers were readily prepared under standard conditions for silylation and reacted with high efficiency with terminal olefins and many types of acetylenes. Internal olefins proved more difficult although the use of phenyl substituents on the silicon atom proximal to the ether tether provided a solution to this problem [137e]. The reaction is stereospecific with syn addition across the reacting group, and also stereoselective. The stereoselectivity of the addition is usually excellent and may be explained by invoking a chair-like T. S. Oxidative cleavage of the silyl ether tether provides an interesting route to 1,2,4-triols - the reaction may therefore be viewed as a directed stereoselective glycolation (Scheme 10-113) [ 137~1.When a trisilanyl ether is used in the bis-silylation of double bonds, the difference in reactivity towards oxidation allows a stepwise oxidation of each C-Si bond (Scheme 10-113) [138]. The bis-silylation reaction has found application in the synthesis of the antifungal metabolite (-)-avenaciolide [ 1391 and in the enantioselective preparation of (E)-allylsilanes [ 1401. The use of chiral isocyanides prepared from the terpenoid (+)-ketopinic acid has also been investigated in an enantioselective bis-silylation of olefins, although the levels of enantioselectivity are, in most cases, modest [ 1411.

10.7.4 Intramolecular Hydrosilylation of Ketones The anti- 1,3-diol motif is widespread among biologically important natural products, and efficient routes towards this unit are desirable. Davis and co-workers have investigated the possibility of using a silyl ether tether to connect a hydridic nucleophile to a phydroxy ketone substrate [142]. Reaction of commercially available 'Pr,SiHCl with a p hydroxy ketone provided the stable silyl ether product 341 in good yield. Subsequent exposure to a variety of Lewis acids effected a highly stereoselective, intramolecular reduction of the ketone group providing the anti-l,3-diol protected as a silyl acetal342, which was sufficiently stable to be used as a protecting group for the diol functionality, yet could also be readily removed with aqueous HF in MeCN (Scheme 10-114). SnCI, gave the best results although a wide variety of Lewis acids and Brgnsted acids were effective (the use of TBAF and zinc Lewis acids gave poor results). The observed stereochemical outcome can be accounted for by invoking a chair-like T.S. in which diaxial interactions with the bulky silyl substituents are minimized. The reaction is not chelation-controlled and does not involve hydride transfer to the Lewis acid since BF, .OEt,, which can only be four-coordinate, also gives excellent anti stereoselectivity. Tethering the reagent and intramolecularizing the process is also important for the rate of reaction - the analogous intermolecular process was found to be sluggish, even at 0 "C. Rhodium(1) complexes also catalyze the reduction reaction. Burk

10.8 Olefnution

37 1 Pr 'Pr

IP~,,'Pr

\

Si-H

I

Si,

CHpClp, -80 "C

342

T.S. leading to antidiol

341

anti : syn 50:l

aq. HF, MeCN

61% (2 steps)

Scheme 10-114 Intramolecular hydrosilylation of Phydroxy ketones provides 1,3-anti-diols.

and Feaster have used chiral diphosphine ligands to provide an enantioselective version of the reaction using a-hydroxy ketones as precursors [143]. The reaction could be extended to Phydroxy esters (Scheme 10-1 15) [ l a ] . In this case, TBAF proved the most effective reagent for providing an almost quantitative conversion to the corresponding alkoxysiladioxanes. Activation of the acetal functionality was best achieved with the superacid [TfOH;B(OTf)J, and trapping with allyltrimethylsilane provided the anti diol products in excellent yield and stereoselectivity. The outcome is in accord with chelation-controlled intermolecular addition with axial attack of the nucleophile onto the cationic oxonium intermediate. P: ,'Pr si-H

O' BU

uoMe

TBAF, 4A ms, CH2C12,0eC,*

98%

pr

'PL Si, 0' 0 BU uOMe

<'

[TfOH$B(OTf)4'],

0 '

1-2 rnol%,

'

-SiMes

'

CHZCIZ,-50"C

6"-

Pr Si,

0

P ':

:Pr Si 0 ' '0

+

Bu

h

anti:synZd:l 85%

Scheme 10-115 Intramolecular hydrosilylation of Phydroxy esters and reaction with ally1 silane provides anti-l,3-diolproducts.

10.8 Olefination The complex structure of the macrolide bryostatin 1, 343, in addition to its activity against various forms of cancer, has made it the subject of a number synthetic studies [145]. One of the more difficult functionalities to incorporate in a stereoselective fashion into the molecule are the two trisubstituted exocyclic unsaturated esters. Evans and Carreira addressed this problem in a novel way by using a tethered phosphonate in a macroolefination reaction (Scheme 10-1 16) [ 1461.

372

I0 Use ofthe Temporary Connection in Organic Synthesis OEt O=&OEt

nOe t )

H

\

H

uo H

bryostatin 1

C02Me

I

345

6-carbon tether optimal

K2C03,MeOH, 76%

H

346

343

Scheme 10-116 The correct choice of tether length ensures stereoselective macroolefination.

Preliminary studies on a model system suggested that a six-carbon tether, which would produce a 14-membered ring, would be optimal in minimizing transannular interactions and satisfying the stereoelectronic requirements of the ester groups (Scheme 10116). Additional computer modeling enabled low-energy conformations of the two diastereoisomeric enoates obtained using such a tether to be evaluated more quantitatively. It was pleasing to see that the desired enoate product was around 10 kcal mol-' more stable than the alternative geometry and the two ester functionalities adopted the preferred s-cis conformation. The calculated enoate dihedral angle (O=C-C=C) of 165" also implied additional stabilization through conjugation. Horner- Wadsworth-Emmons olefination of the model compound 344 provided the desired macrocycle 345 in 86% yield and as a single diastereoisomer. Subsequent basic methanolysis resulted in facile tether cleavage, providing the corresponding hydroxy ester 346. A similarly tethered phosphonate was used to prepare the exocyclic olefin in Danishefsky's synthesis of calicheamicinone 347 [ 1471. Chemoselective acylation of the advanced intermediate 348 provided the olefination precursor 349, and subsequent cyclization gave Slactone 350, enforcing the desired stereochemistry of the double bond. The additional conjugative stabilization of the "exocyclic" olefin with the ester also facilitated subsequent transformations of the azide to the methyl carbamate functionality, and further manipulations ultimately led to the first synthesis of calicheamicinone 347 (Scheme 10-1 17).

10.9 Ullmann Couuline

348

349

373

350

I

0 OH ))--Me

reductive

H O ' e

\\

I/

cleavage

Me0

calicheamicinone 347

Scheme 10-117 A short tether ensures stereoselective incorporation of the exocyclic olefin functionality in calicheamicinone.

10.9 Ullmann Coupling The Ullmann coupling and related reactions provide a useful route to biaryl ring systems [ 1481, which occur in a number of biologically important natural products. Restricted rotation about the C-C bond connecting the two aryl rings leads to the formation of atropisomers, which are frequently configurationally stable even at elevated temperatures. As a result, biaryl systems have also become an extremely important source of chiral ligands for use in asymmetric catalysis. Methods for selectively preparing one atropisomer directly would circumvent the need for a tedious resolution of the racemate, which is the typical method for obtaining enantiomerically pure compounds. A number of research groups have tackled this problem by using a chiral, covalent tether to connect the two reacting aryl groups, thereby taking advantage of the intramolecularization of the process to transmit the asymmetry in the tether to the key C-C bond construction [ 149- 1531. Clearly, if this approach is to compete with resolution protocols, tether formation and subsequent cleavage must be facile and high yielding, and the stereochemical transcription excellent. Lipshutz and co-workers used a variety of readily available chiral diols to tether bromonaphthyl precursors through a bis-ether linkage [149a]. The nature of the tether was found to be crucial for achieving high asymmetric induction. BINOL 351 was prepared using three different tethers with varying degrees of success (Scheme 10-118). Using a

10 Use of the Temporury Connection in Organic Synthesis

314

lactic acid-derived tether (352), the binaphthyl product 353 was formed in 66% e.e., while a tether derived from mandelic acid (354) provided 355 in an improved SO-90% e.e. It was anticipated that increasing the gauche interactions in the tether, which were assumed to account for the stereochemical transcription, would increase the level of asymmetric induction. Diol356, derived from tartaric acid, was therefore twice coupled to 1-bromo-2-naphthol using Mitsunobu reactions, to form the tethered precursor 357. Dilithiation with 'BuLi and treatment with CuCN presumably led to the formation of the higher-order cyanocuprate 358, which on exposure to 0, at 0 "C underwent oxidative coupling, providing a single diastereoisomeric product 359 in 78% yield. Benzylic oxidation with NBS followed by the addition of KOH solution accomplished tether cleavage, providing enantiomerically pure BINOL 351 (Scheme 10-I 18).

i) QuLi ii) CuCN

P

iii) 0

2

352 R = M e 354 R = P h

353 R = Me, 66% d.e. 355 R = Ph, 8040% d.e.

r

351

359

86%

70%

I

i) 'BuLi ii) CuCN 1 2-

358

Scheme 10-118 Appropriate choice of tether provided enantiomerically pure BINOL.

375

10.9 Ullmunn Coupling

Iwasaki and co-workers have used a similar approach to prepare unsymmetrical biaryls [150]. Although they did not address the issue of enantioselectivity, their use of salicyl alcohol 360 as the temporary connection illustrates a number of desirable features in good tether design. The different nucleophilicity of a phenolic, compared with a benzylic, OH group allows the possibility for sequential, regioselective acylation of differently substituted 2-iodobenzoyl chlorides. For example, acylation of 360 with the benzoyl chloride 361 at low temperature proceeded regioselectively on the phenolic position but underwent complete acyl transfer on warming to room temperature to afford ester 362. Without isolation, addition of the benzoyl chloride 363 to the reaction mixture at -20 to -30 "Cprovided the diester 364 in 84%yield (Scheme 10-119). Intramolecular Ullmann coupling also proceeded in excellent yield when a dilute solution of the diester 364 in DMF was added to a suspension of copper powder in DMF at reflux. Regioselective and sequential cleavage of the ester groups might be a desirable process if separate elaboration of each released acid functionality was necessary. Hydrogenolysis proved to be most effective in selectively cleaving the benzylic ester, providing monoester 365 in 82% yield (Scheme 10-119). The salicyl alcohol template has proved to be highly efficient for the synthesis of a wide variety of unsymmetrical diphenic acid derivatives in addition to heterobiaryls [150].

Et3N,cat. DMAP, DMA-CH& 4:1,

' COCl

OH

-30 to -20 "C

*

L

361

380

362

363

-30 to -20 "C

1 n

i

Cu powder,

OMe

385

OMe

DMF, reflux. 89%

82% OMe

OMe

364 78% from 360

Scheme 10-119 Salicyl alcohol is a useful template for the preparation of unsymmetrical biaryls.

I0 Use ofthe Temporary Connection in Organic Synthesis

376

10.10 Use of the Temporary Connection in Carbenoid Chemistry Marsden and co-workers have recently used a-diazo esters tethered through a silyl ether in stereoselective C-H insertion reactions to provide a novel route to 1,2,4-triols [154]. For example, treatment of a-diazo silyl ether 366 with Rh" octanoate generated the corresponding carbenoid species, which underwent I ,5 C-H insertion exclusively into the equatorial C-H bond, providing oxasilacyclopentane 367 after reduction of the ester functionality with DIBALH (Scheme 10-120). It is noteworthy that the initially formed bicycle possesses a trans ring junction, whereas entry to similar systems using radical cyclization almost exclusively provides the cis product. This may be attributed to the avoidance of steric interactions between the cyclohexyl ring and the bulky rhodium catalyst in the insertion reaction. The silicon tether which had served to direct the insertion reaction then had to be unmasked to reveal the desired alcohol functionality. Standard protocols for achieving oxidative tether cleavage led to a competing Peterson-type olefination. Fortunately, the use of hot DMF as solvent alleviated this problematic side reaction, allowing trio1 368 to be isolated in 35% yield from silyl ether 366 (Scheme 10120).

6

,.OH

Et~SiClp. Et3N,

-

Si Et

cat. DMAP, THF,

368

ii) LiTMP, -78 "C

0 "C

70% (from alcohol)

1-3 mol% [13h~(oct)~],

367

P r group omitted

35% from 366

Scheme 10-120 a-Diazo silyl ethers can be used in stereoselective 1,5 C-H insertion reactions.

A similar tethering system was used to functionalize the A-ring of a number of steroidal derivatives regio- and stereoselectively. However, attempts to extend the reaction to acyclic systems were less successful, providing mixtures of diastereoisomers. Transition metal-catalyzed carbenoid insertion into the z system of aryl compounds followed by ring expansion of the resultant E4.1 .O]bicyclohepta-2,4-dieneprovides the

10.11 The Temporary Sulfur Connection

377

best route to tropylidenes. Sugimura and co-workers have shown that a chiral pentane2,4-diol linker can be used to connect a diazo carbenoid precursor with a phenolic substrate to control the regio- and stereochemical outcome of the initial cyclopropanation reaction [ 1551. Phenol-derived diazo ester 369 reacted in the presence of [Rh,(OAc),] with complete regio- and stereocontrol, providing cyclopropane 370.This rearranged stereospecifically to a single, diastereoisomeric cycloheptatriene product 371,which was isolated in 80% yield after column chromatography (Scheme 10-121). The same group have used the same chiral linker to control the regio- and stereochemical outcome of other reactions including a meta arene-alkene photocycloaddition and a diastereodifferentiating E-Z photoisomerization of cyclooctene [ 1561.

369

370

371

Scheme 10-121 A chiral pentane-2,4-diol tether provides a diastereoselective route to tropylidenes.

10.11 The Temporary Sulfur Connection It would be impossible to write a chapter on the use of the temporary connection in organic synthesis without discussing the Eschenmoser sulfide contraction developed by the Eschenmoser group during their pioneering studies towards the total synthesis of vitamin B,, [157, 1581. Disconnecting the corrin nucleus of the vitamin B,, precursor, cobyric acid 372 revealed two similarly sized fragments 373 and 374 (Scheme 10-122). The most convergent route to the preparation of the thioamide fragment 374 entailed cleavage of the vinylogous amidine. The low reactivity of possible reaction partners rendered an intermolecular approach to this bond formation difficult and unviable. Eschenmoser elegantly by-passed this problem by constructing a sulfide bridge between the two reacting centers, bringing them into close proximity and enabling this crucial bond formation [157]. There are two versions of the so-called sulfide contraction although both use a thioamide as the source of sulfur (Scheme 10-123). In the alkylative version [159d, el, the thioamide behaves as a nucleophile, displacing a suitable leaving group a to a ketone and providing thioimino ester 375.In the presence of a suitable base, enolization can occur, allowing nucleophilic attack on the proximal electrophilic imine and generating an episulfide intermediate 376.Treatment with a thiophilic phosphine or phosphite causes extrusion of the sulfur tether, providing vinylogous arnide 377,which is readily con-

378

10 Use of the Temporary Connection in Organic Synthesis

U

cobyric acid

372

I CGMe 373

374

Scheme 10-122 Partial retrosynthesis for vitamin B

verted to the corresponding vinylogous amidine 378. The alternative procedure employs an oxidative coupling protocol to form the sulfide tether [159a, c]. Treatment of thioamide 379 with benzoyl peroxide provides either the disulfide or thiolactam-S-oxide. Whichever is produced, the net result is to make the sulfur sufficiently electrophilic for it to be attacked by the enamide 380, providing the key sulfide intermediate 381. Heating in the presence of a phosphine effects C-C bond formation and sulfur extrusion in one step (Scheme 10-123).In the actual synthesis of amidine 374, the oxidative coupling protocol was used, providing a highly efficient and convergent approach to this key intermediate in the synthesis of the corrin nucleus of cobyric acid 372 [159a]. The ease with which C-S bonds are reductively cleaved makes a sulfide connection an attractive single-atom tether. Moyano, Pericis, and co-workers have used such a linker in their synthesis of (+)-&cuparenone 382 [160]. It was envisaged that the cyclopentanone framework could be accessed using a Pauson-Khand reaction in which the acetylene and alkene components would be tethered through a sulfide bridge. A chiral auxiliary attached to the olefin would impart diastereocontrol on the cyclization, forming a bicyclic product, and the sulfide tether would intramolecularize the process, facilitating the cyclization. The cupped shape of the resulting bicycle would then be exploited in a conjugate addition of a nucleophile from the less hindered convex face, installing the key stereocenter. Reductive cleavage of the sulfur bridge would unmask two methyl groups, with the third being incorporated using standard manipulations. Reaction of enyne 383 with [Co,(CO),] using NMO as a promoter gave an 8 :1 diastereoisomeric mixture of bicycles with the desired (4R,SS)-stereoisomer 384 predominating (Scheme 10-124).

10.11 The Temporary Sulfur Connection

379

alkylative sulfide contraction

$0-

S

ANHBzOOBL 379

oxidative sulfide contraction

I

Or

I

A&

Scheme 10-123 The two versions of the Eschenmoser sulfide contraction.

pMePhLi. Cul. EtZO, 41%

383

b

Ph

I:

major diastereoisomer 384 (d.r. 8 : l )

*

1

-

steps

kcuparenone 382

Scheme 10-124 A sulfide tether was used in the synthesis of p-cuparenone.

i) Ra Ni, EtOH, 95%

ii) Sm12,THF-MeOH. -70"C,90%

$

0

H

380

10 Use qf the Temporary Connection in Organic Synthesis

Conjugate addition of a cuprate generated from p-MePhLi and CuI also proceeded with complete stereocontrol as predicted. Subsequent cleavage of the sulfide bridge with Raney nickel (Ra-Ni) revealed two of the three methyl groups, and further manipulations led to the synthesis of Pcuparenone 382. The same group used a similar approach in the preparation of cis-bicyclo[5.3.0]decan-8-onesand cis-bicyclo[6.3.0]decan-9-ones,providing an entry into the guaiane and homoguaiane classes of natural products [ 1611.

10.12 Metathesis Ring closing metathesis (RCM) has emerged as an important addition to the arsenal of methodologies used in modern organic synthesis and the introduction of readily handled ruthenium catalysts, e.g., 385, by Grubbs and co-workers, has further increased the synthetic utility of this reaction [ 1621. Not surprisingly, the use of temporary tethering protocols in combination with the high efficiency of forming large rings (>12) by RCM, has been explored (see Chapter 9). In a recent example, Grubbs wished to create an all-carbon analog of the cysteine dimer 386, which contains a disulfide bridge [163]. Intermolecular metathesis on (S)-Callylglycine proved ineffective, even under forcing conditions. Once again, the use of a temporary connection proved to be an efficient solution to the problem. By connecting the amino acid monomers to a catechol template 387, RCM proceeded with good efficiency providing the 12-membered macrocycle 388 as a mixture of olefin isomers. Reduction of the olefin mixture and ester hydrolysis led to the desired amino acid analog 389 (Scheme 10-125).

1

i) Pd / C, H2, 96% ii) 3N HCI dioxane (l:l),100 "C iii) propylene oxide, EtOH, 80 "C (95% two steps)

-

Scheme 10-125 A catechol template makes possible the synthesis of a cysteine-dimer analog using RCM.

10.13 Diitz Benzannulation

38 1

Evans and Murthy used RCM of enantiomerically enriched allylic alcohols tethered through a silicon atom to prepare the reduced carbohydrate D-altritol 390 [ 1641. Treatment of diphenylsilyl acetal391 with Grubbs' catalyst 385 in CH,Cl,, heating at reflux, provided the C,-symmetrical silacycle 392 in excellent yield. Dihydroxylation of the cisolefin and simple manipulations led to a facile, expeditious route to D-altritol (Scheme 10-126).

J(-\OTBDps

Grubbs' cat. 385,.

TBDPSO

o\si.o

CH2C12, reflux,

O.si.O

91%

Ph' 'Ph

Ph' 'Ph

391

392 i) 0 ~ 0 4 NMO, , ri ii) TBAF, then Ac20, py. 75%

HO H O*""

OH

OH OH

+

cat. NaOMe, MeOH, rt, 88%

AcO

OAc

Ad*OAc OAc OAc

o-altritol 390

Scheme 10-126 RCM provides a rapid synthesis of ~-altritol.

The mild conditions and high chemoselectivity of the metathesis reaction ensures that a wide variety of temporary connection strategies are compatible, and it is envisaged that this strategy will find increasing use in the future.

10.13 Dotz Benzannulation The benzannulation reaction is a versatile method for the formation of polysubstituted aromatic compounds such as naphthoquinones. This three-component coupling involves the reaction between an qpunsaturated Fischer carbene, an acetylene, and a CO ligand, and initially proceeds by cycloaddition of the alkyne with the carbene complex. The regioselectivity of this step is highly dependent on the substituents on the acetylene moiety and is usually low in the case of internal acetylenes. To overcome potential problems, Semmelhack et al. employed a tethered disubstituted acetylene to control the regioselectivity of the synthesis of the internal six-membered ring in his synthesis of deoxyfrenolicin 393 [ 1651. Fischer carbene complex 394, bearing a pendant acetylene, was reacted in Et,O at 35 to 37 "C for 64 h, and after oxidative

10 Use of the TemDorun, Connection in Ornanic Synthesis

382

workup with DDQ, provided the quinone 395 in 51% yield as a single regioisomer with the correct substitution pattern for subsequent conversion to deoxyfrenolicin (Scheme 10-127). HO Pr

i) 35 "C.64 h, EtzO, ii)DDQ, MeCN, 1 1h h ii) DDQ, MeCN, 51%

\ 5: :$

394

& '/#

0

* *

OMeOH 0

*

steps

4

I

COPH

deoxyfrenolicin 393

Scheme 10-127 A tethered acetylene ensures the correct regiosel ctivity in the benzannulati n reaction.

10.14 Miscellaneous Moeller and co-workers have shown that electrochemically initiated oxidative cyclization between enol ethers and between enol ethers and vinyl or ally1 silanes proceeds with high stereoselectivity (Scheme 10-128) [166]. They envisaged that the use of a temporary tether to connect the reacting partners would provide a stereoselective route to quaternary centers in an acyclic system. A silicon tether was deemed most appropriate since it could be incorporated into one of the reacting partners as a vinylsilane. Accordingly, oxidation of precursor 396 provided a single isomeric product 397 in good yield, demonstrating the compatibility of the silicon tether to the electrolysis conditions (Scheme 10128). In a related study, intramolecular oxidative coupling of enolate derivatives has been investigated by Schmittel and co-workers [ 1671. The intermolecular version of this reaction provides a useful route to 1,4-dicarbonyl compounds but typically suffers from low levels of stereoselectivity. Furthermore, in mixed systems, the desired heterocoupling products are often accompanied by appreciable amounts of homocoupling products. It was hoped that the use of a single metal for both enolate precursors with concomitant intramolecularizationof the bond-forming event might overcome some of these problems.

10.14 Miscellaneous

383

Pt anode, const. current, undivided cell, 2,6-lutidine, LiC104in 10% MeOH-MeCN

65%

replace with temporary connection

O.si

/

,

-

RVC anode, const. current, 2,6-lutidine, 2.0 Fmol-',

72%

Me+%

\'y LiC104 in 50% MeOH-THF)

M

e

0

MeOJ'',

6 0 . p e

I'

J

L

396

397

Scheme 10-128 Electrochemical oxidative cyclization provides a route to stereodefined quaternary centers.

The silyl and titanium bis-enolates 398 and 399 were prepared and treated with a variety of single-electrontransfer reagents. In the case of silyl bis-enolate 398, oxidation with [Fe(phen)J3' provided diketone 400 in moderate yield and good d.e. (Scheme 10129).The titanium analog 399 reacted much more rapidly (1 min; cf. 12 h for 398) under similar conditions - which is in accord with its lower redox potential - but provided a 1 : 1 mixture of meso/dl products. This result once more emphasizes the importance of the nature of the tether when C-C bond formation and tether cleavage both occur during the reaction. C-C bond formation occurs prior to tether cleavage only in the case of silyl enol ether 398, illustrating the increased levels of diastereocontroltypical of an intramolecular process.

os.o i. dPh

\ I

2 eq. [Fe(phen)$+, Phk

% ..Ph

p

+

h

h

P

h

12 h, 57%

398

400

1O:l

CP, ,CP . iT.o dPh

PhL

399

2 eq. [Fe(phen)$+, 1 min, 39%

~

ph $,$Ph

+

-+Ph

1:l

Scheme 10-129 Intramolecular coupling of silyl bis-enolates occurs with good diastereocontrol.

384

10 Use of the Temporary Connection in Organic Synthesis

The rigid, well defined structures of functionalized steroids provide a cheap and readily available source of chiral templates for use in a variety of molecular recognition processes. Maitra and Bandyopadhyay have used methyl 7-deoxycholate as a template in a stereoselective synthesis of the 1,l’-binaphthyl derivative 401 [ 1681. The two hydroxy groups at C-3 and C-12 are suitably sited for attaching naphthyl coupling precursors via ester linkages 402. Oxidative coupling between the naphthol units in 402 was best achieved using [Mn(acac),] in MeCN, providing the binaphthyl product 403 in 65% yield and 65% d.e. Reductive cleavage and in situ acetylation then gave the enantiomerically enriched binaphthyl compound 401 (Scheme 10-130). Thus the steroidal template imparted a moderate degree of diastereoselection on the coupling reaction although further modification of the reaction conditions and the use of different steroid templates could improve the degree of asymmetric induction. The same group have also reported an enantioselective synthesis of Troger’s base using a similar templating strategy [ 1691.

I

0 [Mn(acac)e],MeCN,

i) LiAIH4,THF

*

50 “C, 65%, 65%d.e.

ii) Ac20

HO

major enantiomer 401

HO 402

*

403

Scheme 10-130 Methyl 7-deoxycholateprovides a chiral template for the enantioselective synthesis of the binaphthyl compound 401.

10.15 Concluding Remarks In this review we have tried to give some idea of the importance of the concept of using a temporary connection between two compatible reacting components for organic synthesis. This process of intramolecularizing an event often gives considerable advantages over its intermolecular counterpart and is a fairly established tactic for synthesis. However, although a wide variety of methods are now available for linking the two reactive centers together and, similarly, for eventual removal of the temporary connection, we are not yet using the full power of this method as aprimary design feature in synthesis; rather it is more commonly used to overcome problems encountered during the execution of the initially designed pathway. Nevertheless, as our knowledge increases and more methods become available, we can consider using more imaginative routes based upon the use of the temporary connection. The whole area continues to grow and will become a crucial part of the synthetic planning process in the future.

10.16 Experimental Procedures

385

10.16 Experimental Procedures 10.16.1 Use of an Acetal Tether in Diels-Alder Reactions: IMDA Reaction of Dimethyl Acetal28 (Scheme 10-9) [15] 10.16.1.1 Tether formation Tebbe's reagent (1.35 mL of a 0.50 M solution in PhMe, 0.68 mmol) was added dropwise over 5 min to a solution of acetate 29 (87 mg, 0.62 mmol) in PhMe (0.93 mL), THF (0.3 1 mL), and pyridine (10 pL) at -40 "C.After 15 min, the solution was warmed to rt over 2 h and then stirred for a further 2 h. The reaction mixture was cooled to -10 "C and NaOH (0.19 mL of a 15% aqueous solution) was carefully added. The mixture was warmed to rt and stirring continued until no effervescence was observed. Et,O (8 mL) was then added and the reaction mixture dried (Na,SO,) and filtered through Celite@. Removal of the Et20 in vacuo provided an orange solution, which was further diluted with pentane (30 mL). Filtration through Celite@and removal of the pentane in vacuo provided a yellow solution of the vinyl ether 30 (ca. 0.3 M solution in PhMe) which was used directly in the next step. A solution of methyl 4-hydroxybut-2-enoate 3 (60 mg, 0.52 mmol) in PhMe (1 mL) and [Pd(COD)Cl,] (35 mg, 0.12 mmol) were added sequentially to the solution of 30, and the resulting mixture was stirred at rt for 24 h. Pyridine (20 pL) was then added. The mixture was diluted with Et20 and filtered through Celite@. Removal of the solvent in vacuo provided a yellow oil which was purified by flash column chromatography [Et,O/petroleum ether (40-60 "C boiling point fraction), 1 :41 to yield the triene 28 as a colorless oil (112 mg, 71 %). 10.16.1.2 IMDA reaction and tether cleavage A solution of triene 28 (100 mg, 0.39 mmol) in Et20 was filtered through an alumina column, dried by azeotroping with PhMe (3 x 10 mL) and then redissolved in dry PhMe (15 mL). The resulting solution was degassed by the freeze-pump-thaw technique and then heated at 165"C for 2.5 h in a sealed tube. Removal of the solvent in vacuo provided a mixture of diastereoisomeric cycloadducts (ratio 2.7 :1, 94 mg, 94% mass recovery). Concentrated HC1 (two drops) was added to a solution of the cycloadducts in MeOH (10 mL) and the reaction mixture stirred for 2 h. Solid NaHC03 was then added until effervescence ceased. The solid was removed by filtration and the residue washed with CH2C12.The combined organic fractions were concentrated in vacuo and punfication of the residue by flash column chromatography [EtOAc/petroleum ether (40-60 "C boiling point fraction), 3 : 171 provided the hydroxy lactones 31 and 32 (2.7 : 1, 76 mg, 72%).

386

10 Use of the Temporary Connection in Organic Synthesis

10.16.2 Use of a Boronate Tether in Diels-Alder Reactions: IMDA Reaction between Anthrone 50 and Methyl 4-Hydroxybut-2-enoate3 (Scheme 10-19) [20a] 10.16.2.1 Tether formation and IMDA reaction A solution of methyl 4-hydroxybut-2-enoate 3 (20mg, 0.17 mmol) in pyridine (1.5 mL) was added to a solution of anthrone 50 (33 mg, 0.17mmol) and PhB(OH), (22mg, 0.18 mmol) in pyridine (1.5 mL). The resulting solution was then heated at reflux for 5 h with azeotropic removal of H20. Removal of the solvent in vacuo and purification of the residue by preparative thin layer chromatography (hexane/EtOAc, 3 :1) provided the Diels-Alder adduct 51 (55 mg, 81%), m.p. 218 "C.

10.16.2.2 Tether cleavage A solution of the boronate 51 (38 mg, 0.10 mmol) in THF (3 mL) was added to hydrogen peroxide (30% solution, 5 mL) and the mixture was stirred at rt for 12 h. NaHS04 (1 g) was then added and the product was extracted with CH,Cl, (2x 25 mL). The combined organic extracts were washed with brine and dried (Na,SO,). Removal of the solvent in vacuo and purification of the residue by preparative thin layer chromatography (hexane/ EtOAc, 3 : 1) provided the diol52 (27 mg, 90%), m.p. 136 "C.

10.16.3 Use of the (Bromomethy1)dimethylsilylEther Group in a Radical Cyclization in the Synthesis of Talaromycin A, 140 [54] 10.16.3.1 Tether formation Et3N (40 pL,0.29 mmol) and imidazole (20 mg, 0.29 mmol) were added to a solution of (4R$R)-8-ethy1-4-hydroxy1,7-dioxaspiro[5.5]undec-2-ene (38 mg, 0.29 mmol) in DMF (2 mL) and the resulting solution was stirred for 5 min. (Bromomethy1)dimethylsilyl chloride (40 pL, 0.29 mmol) was then added and the reaction was stirred for 3 h. The reaction was quenched by the addition of NaHC03 solution (satd) and diluted with Et20. The organic layer was washed with brine, dried (MgSO,) and then concentrated in vacuo. Purification of the residue by flash column chromatography (EtOAdhexane, 1: 1) provided the silyl ether 139 as a labile, colorless oil (62mg, 93%).

10.16.3.2 Radical cyclization and tether cleavage (Scheme 10-47) A solution of Bu3SnH (60pL, 0.21 mmol) and AIBN (9 mg, 0.05 mmol) in benzene (1 mL) was added via syringe pump over 2 h to a solution of silyl ether 139 (62 mg, 0.18 mmol) in benzene (4 mL, degassed) heated at reflux. The reaction mixture was heated for a further 5 h and then concentrated in vacuo to provide the crude silacycle, which was used directly: the crude product was added to a mixture of H202 (30% solution, 0.2 mL), NaHC03 (30mg), MeOH (2mL) and THF (2 mL) and the mixture heat-

References

387

ed at reflux for 12 h. After cooling to rt, the mixture was diluted with H20, NaHSO, (10% solution) and NaHC03 (10% solution) and then placed in a continuous extractor and extracted with Et20 for 4 h. Concentration of the Et20layer and purification by flash column chromatography (EtOAc/hexane, 1: 9 to neat EtOAc) afforded talaromycin A, 140 (34 mg, 84%).

10.16.4 Use of Acetals in Intramolecular0-glycosylation: Synthesis of ethyl 2,3,6-Tri-0-benzy1-4-0-(3,4,6-tri-O-benzylP-D-mannopyranosy1)-a-D-glucopyranoside 246 (Scheme 10-77) ~39~1 10.16.4.1 Tether formation pTSA .H20 (5 mg, 0.028 mmol) was added to a cooled (-40 “C) solution of vinyl ether 244 (374 mg, 0.699 mmol) and alcohol 245 (325 mg, 0.699 mmol) in CH2C12(15 mL). The progress of the reaction was carefully monitored by thin layer chromatography and quenched by the addition of Et3N (0.1 mL) when the product spot was major. Concentration of the reaction mixture and purification of the residue by flash column chromatography (EtOAdhexane, 18 : 82 + 0.1% Et3N) provided the acetal243 as a colorless syrup (397 mg, 57%). The product decomposed after extended periods (>24 h) unless stabilized in an organic solvent (CH2C12or EtOAdhexane) with added Et3N (0.5%) (shelflife >2 months). 10.16.4.2 Glycosylation and tether cleavage 4-Me-DTBP (56 mg, 0.028 mmol) was added to a solution of acetal 243 (55 mg, 0.055 mmol) in CH2C12(5 mL) at 0 “C. NIS (62 mg, 0.280 mmol) was then added in one portion and the reaction mixture was allowed to warm to rt. After 18 h, Na,S203 (3 mL of a 0.5 M solution) was added. CH2C12(10 mL) was then added and the resulting solution was washed with H 2 0 (2x10 mL). The phases were separated and the organic fraction dried (MgSO,), filtered, and concentrated. Purification of the residue by flash column chromatography (EtOAdhexane, 2 : 3) provided the disaccharide 246 as a clear syrup (38 mg, 77%).

References [ 11 “Intramolecularization”is used to describe the process of making an intermolecular trans-

formation intramolecular, hence the verb “intramolecularize”;for a previous use see, for example, T.-L. Ho in Tactics of Organic Synthesis, Wiley, New York, 1994, Chapter 6 . [2] G. Stork, H. S. Suh, G . Kim,J. Am. Chen. Suc. 1991,113,7054-7056. [3] (a) M. Bols, T. Skrydstrup, Chem. Rev. 1995,95, 1253-1277; (b) L. Fensterbank, M. Malacria, S. McN. Sieburth, Synthesis 1997, 813-854; (c) D. R. Gauthier, Jr., K. S. Zandi, K. J. Shea, Tetrahedron 1998,54,2289-2238.

388

10 Use qf the Temporary Connection in Organic Synthesis

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Ternplated Organic Synthesis by. Francois Diederich and Peter J. Stang 0 WILEY-VCH Verlag GmbH, 2000

Subject Index

absolute configurations 203 1,5-H-abstraction 322 H-abstraction 3 1 1 , 3 16 acetal-bridged carceplex 107, 108 acetals in intramolecular 0-glycosylation 387 acetal tether in Diels-Alder reactions 385 acetal tethers 284, 285,305 acetal tethers in radical cyclizations 33 1 acrylate oligomerization 22 1 methyl acrylate polymers 227 methyl acrylate telomers 224,229 acrylic acid telomers 224 acrylonitrile 238 activation entropy 275 ACT reactions 225,227,245 ACT sequence 224,228,229 ACT strategy 22 1,227 acyloin condensation 253 adamantanecarboxylate 7 Cexo-trig addition 367 c6, cis-1 addition pattern 210 C, bis-addition patterns 199 c6, C i s - 1 bis-adduct 2 10 C , e,e,e-tris-adduct 190 C , trans-1 bis-adduct 206 C , trans-4 bis-adduct 208 Cm tris-adduct 194 c6, bis-adducts 194, 198 C,, cis-2 bis-adducts 200 C, cis-3 bis-adducts 202 adenine self-pairing 144 (+)-adrenosterone 296, 297 aglycon delivery method 342 alanyl-PNA 143 aldolase mimics 184 alkaline hydrolysis of ester 61 allenes 252 n-allylpalladium species 252,265 (6-allylsilanes 370 allyltributylstannane 222 D-altritol 38 1 aluminum tris(2,6-diphenylphenoxide) 125 Alzheimer’s disease 144 AMBER forcefield 349

amidine binding site 56 amidine groups 61 amidinium benzoate 64 5-amidopyrazole 56 amidopyrazoles 56 amino acid derivatives 49 amino acids 48 1,2-amino alcohols 368 aminoethyl linkage 139, 141, 151 amphiphilic helices 8 amplification 15 1 amyloid diseases 144, 145 anchor-tether-reactive group conjugate 194, 213 androstan-l7#?-ol 162 androstan-3,17-dione 60 androstane-3,17-diol 180, 181 androst-4-ene-3,17-dione 359 anornerically stabilized radical 312 anomeric phenyl sulfones 336 anomeric selectivity 354 methyl 9-anthracenecarboxylate 232 anthracene endcaps 232 anthracenes 189 anthracene-transfer reaction 192 antibodies 45,61 1,3-anri-diols 371 antisense molecules 133 apparent association constants 120 aromatic stacking 137, 146 aromatic substitution 172 aromatic templates 84,90 artificial enzymes 159 artificial proteins 8 asparagine glycoproteins 337 asymmetric cyclocopolymerizations 41,58 1,3-asymmetricinduction 358 asymmetric induction 202 asymmetric Sharpless bis-osmylation 202 asymmetric syntheses 60 autocatalysis 18, 147 (-)-avenaciolide 370 aza-bridged fullerenes 210 1-aza-2-silacyclobutanes 367 azomethine ylide cycloadditions 304

398

Subject Index

,,back-biting'' reactions 230 backbone flexibility 137 backbone-modified nucleic acids I33 bacteria 49,52, 65 Baldwin rules 307 barbiturate drugs 56 base pairing 152 B-DNA 147 B-DNA conformation 140 Beckwith-Houk model for radical cyclization 308 benzannulation reaction 382 p-benzenediazonium sulfonate I73 benzhydryl radical 163 benzo[l8]crown-6 10, 33 benzophenone-4-carboxylicacid 114 benzophenone-4-hexanoic acid 162 benzophenone photochemistry 160, 163 benzophenone-4-propionicacid 161 benzophenones I75 N-benzyl-D,L-valine 55 benzylic ether tether 289 benzylthia-bridged carceplex 1I1 cis-bicyclo[5.3.0]decan-8-ones 380 cis-bicyclo[6.3.0]decan-9-ones 380 bicyclo-DNAs 137 [4.1.O]bicyclohepta-2,4-diene 376 bicyclo[6.3.0]undecane ring skeleton 300 ,,billiard-ball" effect 111 bimolecular rate constant 23 bimolecular termination 239 bimolecular terminators 241 binary RCM catalyst 264 binding constant 25 binding-site interactions 52 Bingel addition 190 Bingel cyclopropanation 189 Bingel macrocyclization 196, 198,201, 213 BINOL 313,374 biological catalysts 152 biological templates 2 biomimetic catalysis 184 biomimetic chemistry 159 biomimetic oxidizing catalysts 180 biopolymers 65 biosynthesis of cholesterol 159 bioxalomycins 304 4,C-bipyridine 11 4,4'-bipyridinium unit 11 2,6-bis(acrylamido)pyridine 56 bis-adduct of c6, 193 bis-adducts of c60 190 bis(alkyny1)methanofullerene 190

bis-aza-fullerenes 2 10 bis(boronic acid)-substituted fullerene 207 bis(carcep1ex) 110 bis-ester tethers 345 bis-ether tether 350 bisimidazoles 55 bis-lactonization 235 bis(o-quinodimethanes) 205 bis( 1 ,10-phenanthroline)copper(II) core 201 boronate template 290 boronate tether in Diels-Alder reactions 386 boronic acid 54,207 boron templates 6 boron-tethered cycloaddition 292 boron tethers 290 branched-chain 1,Cdiols 315 branched-chain 1,5-diols 315 4'-a-C-branched-2'-deoxyadenosines325 C-branched nucleosides 324 branched trisaccharide 349 bridgehead double bond 277,298 a-(bromomethyl)dimethylsilyl ether 308 (bromomethyl)dimethylsilyl ether group in a radical cyclization 386 (bromomethyl)silyl ether connection 33 1 bromosteroid 170 bryostatin 1 371 tert-butyl acrylate 238 di-tert-butylsilyl acetals 279 C, 189 cage compound 7 calicheamicinone 372,373 calix[4]arene-cavitand hybrid carceplexes 112 calix[4]arene/resorc[4]arene carceplex 1 12 calixarenes 112 calixene heterodimers 127 camphanic acid 122 capsules 105,118 7-carbaadenine 144 carbenoid chemistry 376 carbohydrate recognition 206 carbon-acetal tether 285 carbonyl insertion 161 3-carboxybenzisoxazoles 61 carceplexes 10, 105, 106 carcerands 10 carceroisomerism 113 catalytic antibodies 61 catalytic DNA 136 catalytic epoxidations 178 catalytic ring expansion 25 1 catalytic RNA 136

Subject Index catalytic template directed ligation 134 coated silicas 52 catalytic turnover 5,27 cobyric acid 377 catechol template 380 co-conformation 76 [flcatenane 76,78, 81,83, 84 co-conformers 88 [3Jcatenane 86 coenzyme B- 12 184 [4]catenane 86 coiled-coil peptide templates 148 [5]catenane 86 co-monomers 41 [6]catenane 86 compactin 287 [7]catenane 86 conformations of flexible molecules 184 catenane 18 conjugated n-chromophore 189 catenanes 11, 18,75 C,-containing catenane 204 catenate 18 controlled oligomerizations 230 cavitands 109 coordinated template catalysts 183 cavity effect 55 coordination-induced proximity 252 cellobioside 349, 350 coordinative bonds 55 ,,Central Dogma" 133 copolymers 41 cetyl trimethylammonium bromide (CTAB) 175 Corey-Nicolaou method for macrolide chain transfer 221, 224 synthesis 249 chain transfer agent 220,226 comn 377 chain transfer process 229 cortexolone acetate 360 chalcogen-based terminators 236 corticosteroids 167,359,361 charge transfer interactions 11 cortisone 167, 168 chelation-controlled intermolecular addition Cotton effects 203,206 37 1 C-C coupling reactions 249 chemical template 4 covalent template 189 chemosensors 50,64 covalent tether 276 chiral auxiliaries 219 p-cresol 173 c h i d cavities 45,57 cross-catalytic self-replication 147 C6" chiral cis-3 bis-adducts 211 crosslinked polymers 45,48,57 C , chiral functionalization pattern 203 crosslinking agents 45,50 chiral oxazolidine auxiliaries 227 crosslinking polymerization 52 chiral ,,softballs" 122 crown ether formation 249 chiral stationary phase (CHIRALCEL OD@) crown ethers 3 206 crownophanes 254 chiral template molecules 40,42 CTV heterodimers 127 chiroptical properties 57, 203 cubic cyclophane 195 chlorinase 174 cucurbituril 14,18,27 exo-syn chlorination 298 cucurbituril capsules 127 chlorination of anisole 172 Pcuparenone 379 3a-cholestanol 161, 163 (+)-pcuparenone 378 cholestanyl acetate 163 cyanosilylation 368 A9'")-cholestenol 163 cyclic porphyrin dimer I2 A'4-3a-cholestenol 162 cyclic porphyrin oligomers 11 chromatographic resolution 47 cyclic porphyrin tetramer 13 chromatographic supports 52 cyclic porphyrin trimer 12 chromatography 44,58 5-exo cyclization 312,3 13,325 CH-X (X = 0)hydrogen bonding 108 5-exo-dig cyclization 315, 316,333, 336 circular dichroism (CD) 143 5-exo-trig cyclization 308,320,331 circular dichroism (CD) spectra 203 6-exo-dig cyclization 333 circular DNA 150 6-ex0 trig cyclization 328 circumrotation 78, 85 7-endo-trig cyclization 328 clerodin 311 7-exo-dig cyclization 333 clipping reaction 201 endo-re cyclization 305

399

400

Subject Index

endo-trig cyclization 328 cyclization effective molarities 33 6-ex0 cyclization mode 324 cyclizations 2 1 cyclization templates 29 cyclized-DNAs 137 ( 5+2] cycloaddition 303 endo-re cycloaddition mode 306 cycloaddition reactions 276 [5+2] cycloadditions 304 cycloadditions 60 cyclobarbital 56 cyclobutanedicarboxylic acids 60 cyclocholate dimers 127 cyclodextrin 172 a-cyclodextrin 172 Pcyclodextrin 172 cyclodextrin-containing [2]catenane 8 1 cyclodextrin-containingrotaxanes 82 cyclodextrin dimers 127 cyclodextrin inclusion 183 cyclodextrins 81, 178 cycloglycosylation 348 cyclohexyl iodide 222 cyclononylprodigiosin 263 cyclophane 1I , 191 cyclopropanedicarboxylicacids 60 cyclotelomerization 221,226 cyclotrimerization of butadiene 249 cylinder-shaped molecular capsules 125 cysteine-dimer analogue 380 cytochrome P-450 183 cytochrome P-450s 177

dactylol 263 deboronation 42 cis decalin 3 12 decarboxylations 6 1 decarboxylative glycosylation strategy 353 deep-cavity resorcinarene 125 dehydrofluorination 61 demetallation 78 2'-deoxyadenosine 325 deoxyadenosine oligomers 146 methyl 7-deoxycholate template 384 deoxyfrenolicin 382 a-deoxykojic acid 303 2'-deoxy-3'-O-methyluridine 355 2'-deoxyribonucleosides 354,355 /%2'-deoxyribonucleosides 356 2'-deoxyuridine 355 Dess-Martin reagent 228 detoxinine 301

(-)-detoxinine 300, 302 dialkylammonium-containingrotaxanes 9 1 dialkylammonium guests 91 dialkylsilyl tether 283 dialkylvinylsilyl halides 28 I diary1 sulfides 167 diastereofacial selectivity 303, 306 rehi diastereofacial selectivity 306 diastereomeric dyads 42 diastereoselective Binge1 macrocyclization 202 diastereoselective bis-additions 2 11 diastereoselective tether-directed bis-cyclopropanation of C,, 203 diastereoselectivity 199 3,8-diazabicyclo[3.2.lloctane 304 a-diazo silyl ethers 376 dicarbonyl compounds 49 (dichloromethy1)dimethylsilyl ethers 320 Dieckmann condensation of diesters 253 Diels-Alder additions 190, 193, 205,206, 208 Diels-Alder adducts 126,233 Diels-Alder cycloaddition 136, 232,285 Diets-Alder reactions 15, 121,231, 277, 290 Diels-Alder strategy 285 dienyl silyl ethers 28 1, 284 di(ethoxycarbony1)methano addend 190 diglycoluril isomers 123 1,25-dihydroxyvitaminD, 280 dimeric hydrogen-bonded capsules 120 9,lO-dimethylanthracene(DMA) 190 dimethylene sulfone RNA 141 dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) 344 dinuclear macrocycle 83 1 ,S-diol products 325 1,3-diols 309 1,4-diols 309 diols 48 dioxoporphyrins 14 dipeptide-amidopyrazole complex 57 dipeptide template 56 diphenylmethane stoppers 79 diphenylsilyl tether 283 15,16-diphenyl-l,4,7,10-tetraoxa( 10.2)[20]paracyclophan- 15-ene 269 1.3-dipolar cycloaddition 14 diquinane 318 diquinane framework 3 16 directed bis-silylation reactions 369 directed nucleosidations 354 directed stereoselective glycolation 370 C-disaccharides 334,336 distance selectivity 44

Subject Index disulfides 49 4-methyl-2,6-di-rerr-butylpyridine (4-Me-DTBP) 338 divinylbenzene 5 1 dizinc(I1) bisporphyrins 126 DMAP catalysis 235 DNA 2,7, 143 DNA-catalyzed reductive ligation 150 DNA-directed imine formation 148 DNA double helix 133 DNAduplex 29 DNA ligase 136 DNA polymerases 135 DNA replication 14, 105 DNA template 151 A-DNA 147 DNOENMR 238 dodecanedioic acid 176 n-donor character 85 Dotz benzannulation 38 1 double [3+2] cycloadditions 209,210 double Diels-Alder addition 205 double-helical template 150 double helix 18 doubly ion-paired template 176 drugs 49 duplex stability 141 dyes 50 effective molarity 18,25,32, 134, 151 electrochemically initiated oxidative cyclization 382 electrochemical reducibility 193 electrochemical reduction 205 electrolysis 170 electronic structure of the fullerene 205 electron microscopy 145 n-electron ring-current effects 195 electron transfer 205 enantiomeric resolution 48,50,53 enantioselective catalysis 219 enantioselective synthesis 202 enantioselective synthesis of myltaylenol 293 encoded enzymes 149 6-endo addition 327 6-endo cyclization 308, 314, 315,320, 325 endohedral 3He compounds 195 endohedral metallofullerenes 205 endopeptidase inhibitor 267 'O,-ene reaction (the Schenk reaction) 195 energy transfer 205 enthalpy*ntropy compensation 119 enzymes 5, 159

enzyme catalysis 5, 46 enzyme-substrate complex 159 epilachnene 263 equilibrium association constants 12 1 Eschenmoser sulfide contraction 377,379 ester tethers 295 ether-based templates 228 ether tethers 287 ethylene dimethacrylate 5 1 ethylthio donor 347 (4R)-4-ethylvalerolactone 3 12 N-ethyl-4-vinylbenzamide 67 N-Ethyl-4-vinylbenzocarboximide acid ethyl ester 67 exolendo selectivity 283 exponential amplification 147 &facial selectivity 356 ferrochelatase 136 ferrulactone 258 fermlactone I 259 fiber-fiber association 144 fibril 145,152 fibrilarrays 152 fibrillogenesis 15 1 filipinII1 219 Fischer carbene complex 381 Fischer indole synthesis 8 fluoride catalysis 233 fluoromethacrylate-bearingtemplate 239 4-fluoro-4-(4-nitrophenyl)butanone 61 folding topology 8 footprint catalysis 61 force-field calculations 348 B-formDNA 140 N-formylpiperidine 106 fomyl radical equivalent 320 fragmentation-recombination process 326 free-radical addition 219 free-radical halogenations 163 free-radical halogenations of steroids 164 free-radical oligomerizations 219 free-radical polymerizations 236 free-radical reactions 164 fructofuranosides 344 Pfructofuranosides 346 PD-fructofuranosides 344 fullerene+alixarene conjugate 201 fullerene chirality 193 fullerene-crown ether conjugates 205 fullerene dendrimer 201 fullerene-glycodendron conjugate 200 fullerene n-chromophore 195

401

402

Subject Index

fullerene-porphyrin conjugates 201, 205 fullerene properties 189 fullerene radical anion 205 fullerenes 189 C ,, bis-functionalization patterns 204 trans-fused hydrindane 3 10 cis-fused 5,6-ring junction 31 I trans-fused 5,6-ring junction 309,311 gel-like phases 120 genomes 135, 153 Glaser coupling 32 Glaser-Hay coupling 11 (-)-gloeosporone 262, 263,264 a-glucosidation 341 glycoluril 120 a-C-glycoside 333 pC-glycoside 333 glycosyl acceptor 340,353 O-glucosyl/3-mannopyranosides 340 glycosylation 340,349 C-glycosylation 307 0-glycosylation 340 glycosyl donor 340 1,3-glycosyl transfer 353 C-glycosyl transferase 335 0-glycosyl trichloroacetimidates 35 1 graft polymerizations 233 group transfer polymerization 233,234 Grubbs ruthenium carbene catalyst 80 Grubbs-type catalysts 261 guanidinium group 61 guest-determining step (GDS) 107 guest selectivity 107 (ha1oalkyl)dimethylsilyl ethers 3 18 halodesilylation 3 19 ,,head to tail'' isomer 279 heat of formation 193 hemicarceplex 111, 114, 115 hemicarceplexes 105, 114 3He-NMR 195 HETCOR 227 heteroduplex 141 hexadeoxynucleotide template 28 C,, hexakis-adducts 190, 191, 192, 195,212 hexanucleotide template 6 (E)-hex-3-ene-1.5-diyne 199 hexose-oligonucleotides 137 high dilution 266 higher-ordered aggregates 144 HOMO 232 phomoalanyl-PNA 143

homo-DNA (h-DNA) 137 homopropargylic acetylenes 368 Hoogsteen pairing 149 Homer-Wadsworth-Emmons olefination 372 hydantocidin 357 (+)-hydantocidin 356 cis hydrindane 320 trans hydrindane 320 (-)-hydrobenzoin 297 hydrodesilylation 282 hydrogen .abstraction 165 hydrogen atom abstraction 226 hydrogen bonded capsule 108 hydrogen bonding 1 1 , 137 hydrogen bonding interactions 78 hydrogen bonds 94 [C-H---0] hydrogen bonds 84,87,91,95 [N+-H-.O] hydrogen bonds 91 hydrogenolysis 110 hydrolysis of diphenyl carbonate 64 hydropalladation of an allene 267 hydrophobically driven syntheses 8 1 hydrophobically driven syntheses of [2]catenanes 83 hydrophobic side chain interdigitation 146 hydroquinone 11 hydrosilylation 365 hydrosilylation of acetylenes 368 hydrosilylation of allylic amines 367 hydrosilylation of olefins 364 hydroxycarboxylic acids 48 (22R)-22-hydroxycholesterol 3 19,320 phydroxy esters 37 I 22-hydroxylated steroid side chains 314 17a-hydroxyprogesterone 360

IMDA reaction 278,287 imidazole derivatives 49 immobilized template 174 immunoassay 49 immunosorbents 50 immunosuppressive alkaloids streptorubin B 25 1 imprinted cavity 46,60 imprinting template 206,208 inducedfit 53 inherently chiral fullerenes 203 initial rates 29 initiator 23 1 initiator-terminator functionalized template 234 initiator-terminator gap 235,238 initiator-terminator pair 233 A'.3 interactions 277, 316

Subject Index [C-H-n] interactions 84, 87, 108

n-ninteractions 11

inter-bowl hydrogen bonds I15 intercapsular communication process 110 interchromophoric spatial relationship 205 intermolecular associations 152 intermolecular chain-growth polymerization 230 inter-strand hydrogen bonding 146 interweaving templates 18 intramolecular aglycon delivery 343, 344 intramolecular allylation 358, 359 intramolecular Bingel addition 202 intramolecular bis-silylation 369 intramolecular carbopalladation reactions of allenes and alkenes 265 intramolecular carbopalladation reactions of w-haloallenes 25 1 intramolecular chlorination 163 intramolecular coupling of silyl bis-enolates 383 intramolecular [3+ 21 cycloaddition 300 intramolecular delivery of a nitrogen nucleophile 358 intramolecular delivery of the nucleoside base 355 intramolecular Diels-Alder (TMDA) reaction 277 intramolecular epoxidations 171 intramolecular glycosylation 338 intramolecular hydroboration 364 intramolecular hydrogen atom abstraction 229 intramolecular hydrogermylation 364 intramolecular hydrosilylation 364,367,368 intramolecular hydrosilylation of ketones 370, 371 intramolecularization 275,276,307,349,373, 384 intramolecular McMurry coupling 269 intramolecular nucleophile delivery 36 1, 362 intramolecular oxidative coupling of enolate derivatives 382 intramolecular radical cyclization 3 10 intramolecular transformations 275 intramolecular Ullmann coupling 375 in-vitro selections 136 in-vitro selection strategies 134 iodine atom templates 167 iodoaryl template 164 iodonium collidine perchlorate (IDCP) 344 iodonium collidine triflate (IDCT) 344 ion-exchange mechanism 59 ion-paired templates 174

403

ion pairing 177, 266 iron(l1)phthalocyanine 3 iron porphyrin 178 iron tetraphenylporphyrin 183 a-C-isomaltoside 336 methyl a-C-isomaltoside 336 isophorol 321 isophthaloyl chloride 80 isotactic dyad 227 isotactic telomer 227 ivangulin 293 jasmin ketolactone 263 ,jelly donut" 124 ,jelly donut" dimer 123 a-kainic acid 361 Karstedt catalyst 364 Kemp's triacid 18 ketal tether 336 16-keto-3a,5a-androstanol 174 12-keto-3a-cholestano1 161 a-keto-PD-ribonucleosides 325 (+)-ketopinic acid 370 ketyl radical anions 256 key/lock principle 46 kinetic control 95 kinetic deprotonation 297 kinetic templates 5 , 21, 22 knots 18 kojic acid 303 lamination 146 Langmuir monolayers 200 (-)-lardohre 2 19 large carceplexes 109 (+)-lasiodiplodin 263 L-DOPA methyl ester 60 leaving group-based glycosylation 354 leaving group-based intramolecular glycoside bond formation 35 1 leaving group-based intramolecular glycosylation 352 leucine-zipper motif 148 Lewis acid complexes 136 Lewis-acidnewis-base interaction 261 Lewis acid-promoted, M D A cycloaddition 280 ligand exchange chromatography 55 ligation 135, 146 ligation catalyst 151 light initiated polymerization 223 lincomycin 357 linear coupling reactions 21

404

Subject Index

linear oligomers 19 linear porphyrin octamer 20 linear porphyrin oligomers 32 linear templates 14, 22, 23 linear triquinanes 31 7 linear vinyl polymers 40 1,4-linkage 34 1 /3- 1,6-linked disaccharide 339 P 1,4-linked mannoglucoside 338 liquid secondary ionization mass spectrometry 86 locked-nucleic acids (LNAs) 137 lowest unoccupied molecular orbitals 190 low-molecular-weighttemplate 39 low-order hydrogen-bonded aggregates 120 low-valent titanium reagents 253 macrocycle syntheses 259 macrocyclic lactam 79 macrocyclic polyether 85, 90, 91, 94 macrocyclization 220 - metal cation templated 5 macrocyclization rates 228,236 macrocyclization reactions 2 macrocyclizations 228, 238 macro model 349 macro-olefination reaction 37 1 macroporous imprinted polmyers 52 macroporous polymers 45,50 main chain chirality 40 methyl a-C-maltoside 335 Pmannopyranoside linkage 337 Pmannopyranosides 339 Pmannoside formation 340 Pmannoside linkage 342 PD-mannoside linkage 350 Pmannosides 344 ED-mannosides 354 Pmannosylation 345 Masamune-Roush conditions 33 1 mass transfer 53,55,65 materials science 4 McMuny reactions 256 McMuny-type macrocyclizations 254 mechanical bonds 75 mechanically interlocked molecule 75 medium-sized rings 251 mesoporous solids 4 metu arene-alkene photocycloaddition 377 metal-bridged carceplexes 113 metal cations 2 metal cation templates 10, 33 metal-induced self-assembly 1 13

metal ion catalysis 183 metallomacrocycle 90 metalloporphyrin templates 177 metallosalen templates 177 metal nanocylinders 4 metal templates 3, 76 metathesis reaction 261 methyl methacrylate 40 methacrylate polymerizations 233 methacryloyl radical 240 methano[60lfullerenecarboxylic acid 193.212 2-methoxy-4,4,5,5-tetramethyl1,3,2-dioxaborolane 292 3-~-methyl-~-glucofuranose 208 micelles 175 Michaelis-Menten analysis 22 Michaelis-Menten kinetics 63, 134 microparticles 65 microreactors 48,50,60 miniature reaction chamber 126 Mitsunobu reactions 374 MMA oligomerization 240 MM2 calculations 110 Mn3+-porphyrin 180, 18 1 5-em-trig mode 326 modified silicas 44 molar optical rotation 57,58 molecular capsules 105 molecular container 110 molecular dyads 205 molecular dynamics 88 molecular dynamics simulations 140, 142 molecular imprinting 45,47, 208 molecularly imprinted beads 52 molecularly imprinted cavities 64 molecularly imprinted materials 39 molecularly imprinted polymers 48 - catalysis 60 - chromatography 58 molecular mechanics 233,350 molecular mechanics calculations 166,349 molecular nanoscaffolding 195 molecular recognition 135, 137 molecular replication 147 molecular scaffolding 189 molecular square 191 molecular switches 93, 113 molecular switching devices 110 molecular template - definition 4, 33 monolayers 8 - self assembled 9 monomethanofullerene 190

Subject Index monoprotected diols 366 Monte Carlo (MC) conformational searches 349 Mosher esters 232 multiple adducts of C, 189 multiple functionalization 189 m-xylyl-bridgedhemicarceplexes 1I7 myltaylenol 293,294 (NBD),-based template 233 (NBD),-derived template 233, 235, 237 (NBD),-derived template 238 NBD hexameric spacer 233 (NBD)n-based templates 23 1 (NBD), templates 232 nearest-neighbor approximation 140 negative cooperativity 27 ,,negative" template 116 negative templates 20 neutron scattering experiments 145 Nio-catalyzed hydrosilylation 284 nickel(0)-mediated polymerization of norbornadiene 23 I NiCOD,, 231 nicotinic acid 171 nitromethane 342 N-methyl-2-pyrrolidinone (NMP) 107 N,N'-Diethyl-4-vinylbenzamidine 67 N,N-dimethylacetamide(DMA) 106 non-bonding interactions 284 noncovalent bonds 75 non-covalent imprinting 53 non-covalent interactions 47 non-covalent template 189 non-enzymatic oligonucleotide ligations 133 norbornadiene 23 1 norbornadiene oligomers 232 [n]pseudorotaxanes 92 nucleic acid backbone modifications 153 nucleic acid replicators 18 nucleic acids 135 nucleic acid template 151 nucleobase modification 136 nucleosides 49 nucleotides 49 obtusenyne 367 C , octakis(ethy1ester) 195 octalactin A21 258 (-)-octalactin A 259 octanedioic acid 176 olefination 371 oligomeric natural products 2 19

405

oligomerization of methy1 methacrylate 236 oligomerization of methyl methacrylate with template 246 oligomethylene-tethered bis(cyc1opropenone acetals) 209 oligonucleotide biopolymers 153 oligonucleotide catalysts 152 oligonucleotide templates 134, 149 oligopyridine templates 14 oligosaccharide chemistry 337 oligoselective free-radical polymerization ofMMA 237 oligoselective free-radical polymerizations 243 oligoselective polymerization 238 oligoselectivity 233 Olympiadane 86 one-dimensional property transfer 40 OPNA 143 optically active copolymers 41 optically active fullerene derivatives 203 optical rotation 58 organopalladium reagents 252 oxacyclohexadec-11-en-2-one 269 oxazolidine acrylamides 228 oxidative tether cleavage 366 oxophilicity of titanium 256 OXY-PNA (OPNA) 143 palladium-catalyzed alkenyl epoxide cyclization 269 palladium~catalyzed[3+2] cycloadditions 316 paracrystalline materials 144 5-exo pathway 322 Pauson-Khand reaction 378 PEG block copolymer 152 C,, pentakis-adducts 195 pentamidine 56 pentasaccharide 337 peptide-nucleic acids (PNAs) 142 peptide-peptide association 144 peptides 49 A-ppeptides 144 pesticides 50 %facial selectivity 298 phenanthroline-containing rotaxanes 77 phenanthroline ligands 76 phenyl-a-D-mannopyranoside 46 L-phenylalanine anilide 48 L-phenylalanine-anilidetemplate 54 phenyliodine dichloride 163, 164 phenyliodochloride radical 167 phenylseleno glycoside 334 phenylseleno sugars 335

406

Subiect Index

3'-phenylseleno thymidine nucleosides 325 phenylthio a-rhamnosyl donor 347 phenyl3,4,6-tri-O-acetyl- 1-thio-a-glucopyranoside 341 pheromone 2 19 phosphate backbone 153 phosphate esters I84 phosphate substitution 138 phosphodiester formation 151 methylphosphonate derivatives 138 phosphonate esters 50 phosphorothiolate derivatives 138 photochemical [4 +4] cycloaddition 205 photochemical functionalizations 174 photochemical insertion 167 photochemically initiated polymerization 66 photochemical remote functionalization of longchain alkyl esters 160 [2 + 21 photocycloaddition 299 photodimerization of a norbornene precursor 233 photoinduced intramolecular pinacolization 254 E-Z photoisomerization 377 photolysis 165 photonic crystals 4 phthalocyanine 6 phthalyl 347 PMB acetal tether 344,346 p-methylanisole 173 PNA 143 PNA-DNA-PNA triple helix 142 polyene macrolide antibotics 219 polyether template 229 polymerase chain reaction 149 polymeric materials 45 polymeric template 39 polymerization 5 1 polymers 51 polymer-supported glycosyl donor 345 polynorbomane-based template 230 polyols 48 polyquinanes 3 16 poly(triacety1ene) oligomers 199 porphyrin-cyclodextrin conjugates 179 porphyrin-fullerene conjugates 205 porphyrin luminescence 205 porphyrin metallation 136 porphyrins 126 ,,positive" template 116 precapnelladiene 299 precatenanes 76 preorganization 126, 134

prerotaxanes 76 5-exu-trig process 3 15 product dissociation 149 product distribution analysis 22 product histogram 225 product histogram for ACT 229 product-template duplex 135 property transfer 40 propionaldehyde homoenolates 362 prostaglandin F,, 33 1 proteins 49 pseudo-dilution effect 266 pseudo-octahedral addition pattern 194 [3]pseudorotaxane 9 1 [4]pseudorotaxane 91 [5]pseudorotaxane 91 [2]pseudorotaxanes 85,95 Pt-catalyzed intramolecular hydrosilylation 368 purine derivatives 49 pyranosyl-RNA (p-RNA) 137 pyrazine 107 pyridine-based tethered templates 169 pyridoxal 184 pyridoxal phosphate 184 pyridoxamine 184 pyridoxamine phosphate 184 2-pyridyl sulfones 336 pyrrolizidine alkaloids 300 o-quinodimethanes 291 racemic dyads 42 racemic resolution 46 radical acceptor 323 6-en0 radical cyclization 332 9-endo-trig radical cyclization 335, 336 radical cyclization 42, 309,3 10,312, 3 18 radical cyclization of (1 -bromovinyl)dimethylsilyl ethers 322 radical cyclization of silyl acetals 329 radical cyclization on the 2',3'-diol 330 radical cyclization onto a double bond 308 radical cyclization onto a triple bond 3 15 radical cyclization reactions 307 radical cyclizations 307, 308 radical halogenations 192 radical polymerization of activated alkenes 234 radical relay chlorination 166 radical relay mechanism 164 radical relay process 163, 165 radical traps 33 1 radioimmunoassays 65 rapamycin 366, 367

Subject Index rate-determining step 109 rate enhancement 22,25, 30 RCM-based macrocyclizations 26 1 RCM-based ring closure reactions 259 reductive amination 7 reductive cleavage strategy 294 reductive coupling of carbonyl compounds 253 reductive desilylation 3 10 Reformatsky reactions 258 regio- and stereo-controlled glycosylation 347 regioselective bis-functionalization 209 regioselective enolate formations 258 regioselective functionalization 192 regioselective hydroxylation 181 regioselective IMDA reaction 291 relay chlorine transfer 173 relay model 261,263 remote functionalization 162 remote glycosylation reactions 345, 350 remote glycosylation strategy 349,354 remote intramolecular glycosylation 345 removal of the tether 213 replication cycle 151 replication fidelity 135 resorcinarene 112 resorcinarene-based cages 127 retro aldol fission 300 retro Diels-Alder process 294 retro-Diels-Alder reaction 195 reversed-phase HPLC 52 reversible covalent templates 189 (L)-rhamnal-derived silyl ether 3 12 EL-rhamnoside 348 EL-rhamnoside linkage 350 @-rhamnoside linkages 347 p-L-rhamnosides 354 rhizoxin 332 ribonucleoside 329 ribose modifications 137 ribose-modified nucleic acids 138 ribozymes 134, 136, 152 rigidmatrix 43 ring closing metathesis (RCM) 259,380 ring closure reactions 249 ring-opening and ring-closing methathesis (RORCM) 80 RNA 2 RNAseP 134 RNA synthesis 14 RNAworld 152 ,,RNA-world 136 roseophilin 263,266 [2]rotaxane 77, 87

407

rotaxane 18, 27 [2]rotaxanes 79,88 rotaxanes 11,75 rSNA 141 ruthenium(1I)carbonyI porphyrins 14 saccharide template 208 Saegusa oxidation 332 Sakurai coupling 288 salicyl alcohol template 375 salt bridge formation 146 samarium iodide 258 scavenger templates 19 selection methods 136 selective hydroxylation 180 self-assembled block copolymer aggregates 127 self-assembling calix[4]resorcinarene oligomers 127 self-assembling reversible capsules 119 self-assembly 8, 204 self-association of amyloid peptides 145 self-complementary hexamer 147 self-complementary sequences 137 self-replicating system 17, 29 self-replication 15 self-replicator 27 semi-empirical PM3 calculations 193 sensor 48 separation factor a 46 serine proteases 166 @sheet conformation 56 Psheet template 152 shell-closure reactions 106, 111, 1 15 sila-hexenyl radicals 3 14 silicon anomeric effects 328 silicon-tethered ene cyclization 362, 363 silicon-tethered ene precursors 363 silicon-tethered radical cyclization 3 13 silicon tethers 278, 296 silicon transfer oligomerization 235 siloxane bonds 44 siloxane template 367 silyl acetals 278,296,327,328 silyl acetals as the tether-directing group 339 silyl acetal tether 280, 330 silylacetate 239 silyl ethers 296 silyl ether tethers 321, 325 silylformylation 368 silyl tether 301 silyl-tethered radical cyclization 312 silyl-tethered radical cyclization of nucleosides 326

408

Subject Index

silyl-tethered radical cyclizations 3 15,323 singlet oxygen ene reaction 193 singlet oxygen photosensitization 193 slippage processes 89,90 SmI,-mediated Reformatsky reaction 258 S,N-acyl rearrangement 148 sodium dodecylsulfate (SDS) 175 ,,softball" 121 ,,softball" dimers 122 ,,softballs" 119 solid-phase synthesis 141 solid-phase synthesis of amide-linked oligonucleotides 142 solid-state template effect 192 solvation requirements 153 solvent effects 110,239 solvent-induced steric effect 243 solvent-solute interactions 241 solvophobic effect 243 space occupancy factor 125 specificity constant I35 square root law 18 [n-n] stacking 84,91 statine 323,324 stationary phases 58 stationary phases in chromatography 64 statistical reaction 22 Steglich/Keck conditions 235 stereochemical descriptors 'C and 'A 203 stereochemical transcription 276 stereocontrolled synthesis of 22-hydroxylated steroids 314 stereocontrol on the IMDA reaction 289 stereodefined quaternary centers 383 stereoelectronic restraints 212 stereoisomerism 113 in-in, in-out, and out-out stereoisomerism 200 stereoisomer separation 23 I stereoregular copolymer 40 stereoselective 1 3 C-H insertion reactions 376 stereoselective C-H insertion reactions 376 stereoselective glycosylation 337,342,35 1 stereoselective intramolecular glycosylation 343 stereoselective macroolefination 372 stereospecific methylation of steroids 3 10 steroid hydroxylations 180 steroids 49, 309 stoechospermol 299 A1v3-strain 305 strand association energetics 140 @strand peptides 144 strand-strand association 152 subphthalocyanine 5

substituted vinylsilyl ether 322 substrate assembly 4 substrate-directed stereoselective synthesis 276 substrate selectivity 44 substrate-substrate bonding 8 substrate-template ternary complex 135 succinyl ester tethers 347 sugar pucker 147 sugars 48 sugar template 207 sulfide tether 303 sulfonate tether 293 sulfonate tethers 292 sulfoxide and sulfone tethers 304 sulfur templates 167 sulfur tethers 303 superphthalocyanine 6 supramolecular advanced materials 193 supramolecular aggregates 144 supramolecular chemistry 76, 105 supramolecular complex 93 surface imprinting method 52 surface of silica 44 surfactant mesophases 4 suspension polymerization 52 synthesis of C-glycosides 333 talaromycin A 312, 313, 386 Tamao oxidation 308,312,316,325 tandem [4 + 2143 + 21 cycloaddition 302 tandem [4+2]/[3 + 21 nitroalkene cycloaddition reactions 300 tandem [4+2]/[3+2] reaction 300 Taxol 258,259,292 Tebbe methylenation 284,335 telomer 220,226 telomer assay 225,229,245 telomer distribution histogram 222 telomerizations 230 telomerization terminator 220 telomer length 223 template - forcyclization 10 - substrate interactions 8 template autonomy 135 template backbone 230 template-bound pMMA 239 template-bound radical 242 template-bound silyl ketene acetal initiator 239 template controlled free-radical oligomerization 238 template controlled free-radical oligomerization ofMMA 243

Subject Index template controlled oligomerizations 2 19,237 template controlled oligoselective free-radical polymerization of methyl methacrylate (MMA) 237 templated bis-functionalizdtion 206 templated cyclization reactions 253 templated Diels-Alder reaction 26 templated ex0 Diels-Alder reaction 27 template-directed chlorination 170 template-directed epoxidations 172 template directed ligation 134, 148, 153 template directed ligation polymerization 152 template directed polymerization 133 template-directed reaction 193 templated radical macrocyclization 220, 22 1 template effect in ring closure reactions 258 template effect of low-valent-titanium [Ti] 257 template effects 3, 114 template efficiency 29 template efficiency parameters 26 template-free methyl acrylate telomerization 224,225 template mediated free-radical oligomerization ofMMA 238 template mediated oligoselective polymerization of MMA mechanism 240 template monomer 65 template polymerization 39 template ratios 107 templates - for macrocyclization 10 template-substrate complex 149 ternplating saccharide 207 temporary boronate tether 292 temporary connection 275 temporary sulfur connection 377 temporary tethering strategies 276 ,,tennis balls" 119, 120 terminator 23 1 terminator challenge experiments 241 terminator performance 236 ternary complex 14, 15,23 terpene polyenes 172 terpenoid, marine natural product 298 tertiary structural folds 153 tether-directed allylation 360 tether-directed functionalization methods 192 tether-directed intramolecular glycosylation 351 tether-directed /?-Omannoside syntheses 335 tether-directed radical cyclization 323, 333 tether-directed remote functionalization 189 tethered acceptor 338

409

tethered acetylene 382 tethered bis-azides 2 10,21 1 tethered bis(/%keto ester) 201 tethered bis(buta- 1,3-diene) 205 tethered bis(buta- 1,3-diene)s 205 tethered radical cyclization 3 I9 tethered reactions 8.29 tethered reagents 163 tethered vinylcarbenes 209 tether-mediated nucleophile delivery 356 tether-reactive group con'ugate 193, 212 tetraazacyclononane-CJ+ chelates 55 tetraazamacrocycles 3 tetraethynylated C,, hexakis-adduct 196 tetrahedral transition state 62 C,, tetrakis-adducts 195 tetrameric assembly 124 tetramethylene dimethacrylate 5 1 tetrapyridylporphyrin 13,20 tetrapyridylporphyrin template 26 tetrarylmethane-based stoppers 88 tetrol bowl 107, 116 tetronolide 285 theoretical plates 59 thermally initiated polymerization 66 thermal [2 + 2 + 21 retro-cycloaddition 205 thermodynamic control 81,95 thermodynamic cycle 148 thermodynamic template 5,7 thexylborane 29 1 thiamine pyrophosphate 184 thiazolium ions 184 thiophenyl-bearing template 238 thiopyridyl esters 249 thioxanthone tethered template 168 Thorpe-Ingold effect 303 Thorpe-Ziegler dinitrile method 253 three-dimensional molecular scaffolding 2 11 three-dimensional transfer of information 45 three-electron bond 169 three-point binding 56 thymidine nucleosides 324 titanium-induced intramolecular carbonyl coupling reactions 253 titanium mediated coupling of allylic alcohols 256 topochemical solid-state synthesis 192 topochemistry 46 topological information 18 topological stereoisomers 82 topological templates 28 tosyliminoiodobenzene 183 transannular interactions 277,328

410

Subject Index

transesterification 204,213 transition state analogue 61 transition state imprinted polymer 63 transition state models 107, 119 transition state solvation 11 3 transition state stabilization 5 translational entropy 166 trefoil knot 18, 19 triazole stoppers 91 tribenzyl-levoglucosan 342 trichloroacetate template moiety 236 tricolorin A 263 tricolorin G 263 tricyclic plactam antibiotics 358,359, 360 tricyclo-DNAs 137 trifluoroacetate 238 trile-helical structures 142 trimer carceplex 1I0 1,2,3-trimethoxybenzene I1 8 trimethylenemethane 3 16 trimethylol trimethacrylate-based beads 52 2-[(trimethylsilyl)methyl]prop-2-en-l-ol 3 16 2-(trimethylsilyl)oct-l-en-3-one 331 2,4,6-trinitrophenyl stoppers 83 methyl 2,3,6-tn-O-benzy1-4-0-(3,4,6-tri-Obenzy~-fiD-manno-pyranosyl)-a-~-glucopyranoside 387 1,2,4-triols 369, 370 triple helix 149 triply tethered template 169 tripyridyltriazine 11 triquinane 318 Troger's base 384 tropylidenes 377 Tsuji-Trost allylation 265 tunicarnycin V 328, 329, 330 turnover number 134 turnover rates 152 two-dimensional information transfer 42 two-point binding 56,58, 180 type I1 IMDA reactions 295

Ullmann coupling 373 unsymmetrical biaryls 375 uranyl templates 6 urea-based calixarene dimers 126 UV hyperchromism 140 van der Waals contacts 108 van der Waals interactions 9, 121 van der Waals surface 140 vapor-phase osmometry 113 vesicles 175 vinyl acetate 238 vinylcarbenes 209 vinylene carbonate 238

4-vinyl-N,N'-diethylphenylamidine 56 4-vinylphenylboronic acid 46 4-vinylphenylboronic acids 40 vinyl polymerizations 40 vinyl silanes 281 vinyl silyl ether IMDA reactions 283 vinyl silyl ethers 281 vinyl sulfonates 292 vitamin B,, 377, 378 Vorbriiggen coupling 356 Wadsworth-Emmons homologation 33 I Watson-Crick base-pairing 140 Watson-Crick base pairing rules 137 Watson-Crick duplexes 137 Weinreb amide 366 wide-pore silica 42 Wieland-Miescher ketone 296 ,,wiffle balls" 119, 121, 122 Wilkinson's catalyst 364 Wittig reaction 332 p-xylylenediamine 80 zearanol 263 zeolites 4 Ziegler-Ruggli dilution principle 254 zwitterionic tetrahedral intermediate 122